Materiały źródłowe

• #1 Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2422955/

  Renal cell carcinoma (RCC), the fifth leading malignant condition for men and tenth for women, accounts for 3% of all malignancies in Canada. […] Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for this disease. […] Significant developments in understanding the underlying genetic basis of RCC over the last 2 decades are attributed to intensive research about rare inherited renal cancer syndromes and the identification of the genes responsible for them. […] The study of renal cancer genes and their molecular mechanisms is of utmost importance because it may help identify targets for therapy that will improve survival. […] Inactivation or loss of the wild-type VHL allele results in failure to bind with HIF-1. Consequently, HIF-1 accumulates under normoxia, translocates from cytoplasm to nucleus and subsequently heterodimerizes with HIF-1 to enable binding to an HIF-responsive element and induce transcription of target genes leading to the production of GLUT-1 glucose transporter, platelet-derived growth factor, carbonic anhydrase genes CA IX and CA XII, vascular endothelial growth factor, and transforming growth factor, thereby contributing to renal carcinogenesis.

• #2

  https://cuaj.ca/index.php/journal/article/view/63

  Renal cell carcinoma (RCC), the fifth leading malignant condition for men and tenth for women, accounts for 3% of all malignancies in Canada. […] Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for this disease.

• #3 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. […] In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. […] The most common genetic alteration associated with the development of ccRCC is loss of the short arm of chromosome 3 (loss of 3p). […] The most common genes involved in the pathogenesis of ccRCC include VHL, PBRM-1, SETD2, BAP-1, KDM5C, and MTOR. […] VHL is a tumor suppressor gene that plays a pivotal role in the development of ccRCC. […] It is estimated that 50-60% of patients with sporadic ccRCC have an abnormality of the VHL gene.

• #4 Kidney cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/kidney-cancer/symptoms-causes/syc-20352664

  Kidney cancer happens when cells in the kidney develop changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions tell the cells to die at a set time. In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to make many more cells quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells. […] The cancer cells form a mass called a tumor. The tumor can grow to invade and destroy healthy body tissue. In time, cancer cells can break away and spread to other parts of the body. When cancer spreads, it’s called metastatic cancer.

• #5 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. […] In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. […] The most common genetic alteration associated with the development of ccRCC is loss of the short arm of chromosome 3 (loss of 3p). […] The most common genes involved in the pathogenesis of ccRCC include VHL, PBRM-1, SETD2, BAP-1, KDM5C, and MTOR. […] VHL is a tumor suppressor gene that plays a pivotal role in the development of ccRCC. […] It is estimated that 50-60% of patients with sporadic ccRCC have an abnormality of the VHL gene.

• #6 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Over the past decade, our understanding of the biology and pathophysiology of renal cell carcinoma (RCC) has improved significantly. […] In this article, we review the various genetic and immune-related mechanisms involved in the pathogenesis and development of this cancer and how that knowledge is being used to develop therapeutic targeted drugs for the treatment of RCC. […] The most common genetic alteration associated with the development of ccRCC is loss of the short arm of chromosome 3 (loss of 3p). […] The most common genes involved in the pathogenesis of ccRCC include VHL, PBRM-1, SETD2, BAP-1, KDM5C, and MTOR. […] VHL is a tumor suppressor gene that plays a pivotal role in the development of ccRCC. […] It is estimated that 50-60% of patients with sporadic ccRCC have an abnormality of the VHL gene.

• #7 Renal Cell Carcinoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/281340-overview

  Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy. […] The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). […] Mutations of the VHL gene result in the accumulation of hypoxia-inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

• #8 Renal Cell Carcinoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/281340-overview

  Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy. […] The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). […] Mutations of the VHL gene result in the accumulation of hypoxia-inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

• #9 Renal Cell Carcinoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/281340-overview

  Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy. […] The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). […] Mutations of the VHL gene result in the accumulation of hypoxia-inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

• #10 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Other, more sophisticated studies have suggested that VHL gene alterations through genetic and epigenetic mechanisms can be found in up to 90% of ccRCC cases. […] A two-hit hypothesis has been described and validated in patients with VHL disease-related development of RCC (and other tumors). […] The product of the VHL gene is a protein called pVHL, which acts as a tumor suppressor protein. […] One of the major functions of the VHL gene product is regulating the levels of several intracellular proteins, including hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A and HIF2A). […] Under conditions of hypoxemia or in the absence of pVHL, hydroxylation of HIF1A and HIF2A does not occur and HIFA accumulates in the cell and dimerizes with hypoxia-inducible factor beta (HIFB). […] The mTOR pathway starts with the binding of several growth factors to the cell surface, resulting in the activation of phosphatidylinositol-3-kinase (PI3K) protein.

• #11 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Other, more sophisticated studies have suggested that VHL gene alterations through genetic and epigenetic mechanisms can be found in up to 90% of ccRCC cases. […] A two-hit hypothesis has been described and validated in patients with VHL disease-related development of RCC (and other tumors). […] The product of the VHL gene is a protein called pVHL, which acts as a tumor suppressor protein. […] One of the major functions of the VHL gene product is regulating the levels of several intracellular proteins, including hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A and HIF2A). […] Under conditions of hypoxemia or in the absence of pVHL, hydroxylation of HIF1A and HIF2A does not occur and HIFA accumulates in the cell and dimerizes with hypoxia-inducible factor beta (HIFB). […] The mTOR pathway starts with the binding of several growth factors to the cell surface, resulting in the activation of phosphatidylinositol-3-kinase (PI3K) protein.

• #12 Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2422955/

  Renal cell carcinoma (RCC), the fifth leading malignant condition for men and tenth for women, accounts for 3% of all malignancies in Canada. […] Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for this disease. […] Significant developments in understanding the underlying genetic basis of RCC over the last 2 decades are attributed to intensive research about rare inherited renal cancer syndromes and the identification of the genes responsible for them. […] The study of renal cancer genes and their molecular mechanisms is of utmost importance because it may help identify targets for therapy that will improve survival. […] Inactivation or loss of the wild-type VHL allele results in failure to bind with HIF-1. Consequently, HIF-1 accumulates under normoxia, translocates from cytoplasm to nucleus and subsequently heterodimerizes with HIF-1 to enable binding to an HIF-responsive element and induce transcription of target genes leading to the production of GLUT-1 glucose transporter, platelet-derived growth factor, carbonic anhydrase genes CA IX and CA XII, vascular endothelial growth factor, and transforming growth factor, thereby contributing to renal carcinogenesis.

• #13 Novel drug targets tumor growth in advanced kidney cancer — Harvard Gazette

  https://news.harvard.edu/gazette/story/2020/02/novel-drug-targets-tumor-growth-in-advanced-kidney-cancer/

  Scientists report promising activity of a novel drug that targets a key molecular driver of clear cell renal cell carcinoma in patients with metastatic disease. […] The drug targets a component of the bodys mechanism for sensing oxygen levels and turning on genes that enable the body to adjust to hypoxia a shortage of oxygen by making more red blood cells and forming new blood vessels. […] In the vast majority of patients with clear cell renal carcinoma, a tumor suppressor protein known as Von Hippel-Lindau (VHL) is not functional. As a result, HIF proteins accumulate inside the tumor cell, wrongly signaling a shortage of oxygen, and activating the formation of blood vessels, fueling tumor growth. Understanding this abnormal process has paved the way for new cancer drugs. MK-6482 is one of them, and is distinct in that it targets HIF-2a directly, leading to blocking cancer cell growth, proliferation, and abnormal blood vessel formation.

• #14 Novel targeted drug shows promise in advanced kidney cancer

  https://www.dana-farber.org/newsroom/news-releases/2020/novel-targeted-drug-shows-promise-in-advanced-kidney-cancer

  Scientists report promising activity of a novel drug that targets a key molecular driver of clear cell renal cell carcinoma (ccRCC) in patients with metastatic disease. […] The drug targets a component of the bodys mechanism for sensing oxygen levels and turning on genes that enable the body to adjust to hypoxia a shortage of oxygen by making more red blood cells and forming new blood vessels. […] In the vast majority of patients with clear cell renal carcinoma, a tumor suppressor protein known as Von Hippel-Lindau (VHL) is not functional. As a result, hypoxia inducible factor (HIF) proteins accumulate inside the tumor cell, wrongly signaling there is a shortage of oxygen, and activating the formation of blood vessels, fueling tumor growth. Understanding this abnormal process has paved the way for new cancer drugs MK-6482 being one of them and is distinct in that it targets HIF-2a directly leading to blocking cancer cell growth, proliferation, and abnormal blood vessel formation.

• #15 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  Other, more sophisticated studies have suggested that VHL gene alterations through genetic and epigenetic mechanisms can be found in up to 90% of ccRCC cases. […] A two-hit hypothesis has been described and validated in patients with VHL disease-related development of RCC (and other tumors). […] The product of the VHL gene is a protein called pVHL, which acts as a tumor suppressor protein. […] One of the major functions of the VHL gene product is regulating the levels of several intracellular proteins, including hypoxia-inducible factor 1 alpha and 2 alpha (HIF1A and HIF2A). […] Under conditions of hypoxemia or in the absence of pVHL, hydroxylation of HIF1A and HIF2A does not occur and HIFA accumulates in the cell and dimerizes with hypoxia-inducible factor beta (HIFB). […] The mTOR pathway starts with the binding of several growth factors to the cell surface, resulting in the activation of phosphatidylinositol-3-kinase (PI3K) protein.

• #16 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  The mammalian target of rapamycin (mTOR) is a protein kinase that is encoded by the MTOR gene. […] Everolimus and temsirolimus are mTOR inhibitors that are approved for the treatment of metastatic ccRCC. […] The cytotoxic component of the immune system plays a vital role in the recognition and subsequent rejection of several different types of cancer, including RCC. […] Several cancers, including ccRCC, express PD-L1 on their surface. […] The expression of PD-L1 allows these cancers to escape the cytotoxic immune response by inducing the apoptosis of cytotoxic T lymphocytes. […] A better understanding of the biology and pathogenesis of ccRCC has revolutionized the treatment approach. […] With a greater understanding of the pathogenesis of RCC, many therapeutic advances for metastatic disease have been introduced in the last decade.

• #17 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The use of cell lines for cancer modeling has several limitations. […] In recent years, 3D co-culture systems were developed and provided highly physiological systems and a more sophisticated platform for disease modeling and drug screening. […] Tumor xenograft models are essential approaches to research the pathogenesis and treatment of RCC. […] Novel kidney models, such as organoids, enable the precise analysis of the influence of specific genetic or molecular alterations on the development of drug resistance, including the effect of the tumor microenvironment. […] The phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway controls nucleotide and protein synthesis, translation, glucose/lipid metabolism, cell survival, and proliferation and thereby has a crucial role in cell growth, differentiation, survival, metabolism, migration, and angiogenesis of tumor cells.

• #18 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  Dysregulation of this signaling pathway was reported in different types of RCC and is related to metastasis and lower survival rate. Therefore, pharmacological inhibitors of the PI3K/AKT/mTOR signaling cascade are promising drug candidates for RCC. […] Most studies have focused on studying ccRCC, and there are only limited studies focusing exclusively on nccRCC. […] In localized non-clear RCC, surgical practice is the most important and probably the only treatment approach. […] Metastatic non-clear RCCs are very challenging cancers to treat, and because there is no standard of care, there is disagreement amongst professionals regarding the best therapeutic option for these patients. […] Currently, cytokine therapy is not an effective treatment for nccRCC histology. […] nccRCC patients are currently treated with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and mTOR inhibitors.

• #19 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  Dysregulation of this signaling pathway was reported in different types of RCC and is related to metastasis and lower survival rate. Therefore, pharmacological inhibitors of the PI3K/AKT/mTOR signaling cascade are promising drug candidates for RCC. […] Most studies have focused on studying ccRCC, and there are only limited studies focusing exclusively on nccRCC. […] In localized non-clear RCC, surgical practice is the most important and probably the only treatment approach. […] Metastatic non-clear RCCs are very challenging cancers to treat, and because there is no standard of care, there is disagreement amongst professionals regarding the best therapeutic option for these patients. […] Currently, cytokine therapy is not an effective treatment for nccRCC histology. […] nccRCC patients are currently treated with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and mTOR inhibitors.

• #20 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  The mammalian target of rapamycin (mTOR) is a protein kinase that is encoded by the MTOR gene. […] Everolimus and temsirolimus are mTOR inhibitors that are approved for the treatment of metastatic ccRCC. […] The cytotoxic component of the immune system plays a vital role in the recognition and subsequent rejection of several different types of cancer, including RCC. […] Several cancers, including ccRCC, express PD-L1 on their surface. […] The expression of PD-L1 allows these cancers to escape the cytotoxic immune response by inducing the apoptosis of cytotoxic T lymphocytes. […] A better understanding of the biology and pathogenesis of ccRCC has revolutionized the treatment approach. […] With a greater understanding of the pathogenesis of RCC, many therapeutic advances for metastatic disease have been introduced in the last decade.

• #21 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The results of clinical trials evaluating the efficiency of TKI pharmaceutical agents in nccRCC are controversial. […] The binding of two cell surface receptors of immune cells, programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), to their ligands on tumor cells results in inhibiting the cellular immune response. […] Therefore, the ICIs targeting PD-1/PD-L1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) are approved to treat RCCs. […] Given the highly invasive nature and poor outcomes of this disease, there is an urgent need to identify the molecular signature and therapeutic targets.

• #22 Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2422955/

  pVHL has been involved in numerous cellular processes such as regulation of the extracellular matrix (ECM); cytoskeletal stability; and cell-cycle control and differentiation, other than regulation of HIF. […] Loss of VHL function leads to abnormalities in the deposition of extracellular fibronectin, a glycoprotein that interacts with integrins to bridge cells to the structural proteins of the ECM. […] The activation of c-MET in HPRC was found to possess constitutive kinase activity and malignant transforming ability. […] In renal cancer, the MET and VHL signaling pathway is thought to intersect by means of pVHL-mediated regulation of HIF function. HIF stabilization through hypoxia or loss of VHL function results in overexpression of c-MET and forms a synergistic effect in inducing invasion.

• #23 Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2422955/

  pVHL has been involved in numerous cellular processes such as regulation of the extracellular matrix (ECM); cytoskeletal stability; and cell-cycle control and differentiation, other than regulation of HIF. […] Loss of VHL function leads to abnormalities in the deposition of extracellular fibronectin, a glycoprotein that interacts with integrins to bridge cells to the structural proteins of the ECM. […] The activation of c-MET in HPRC was found to possess constitutive kinase activity and malignant transforming ability. […] In renal cancer, the MET and VHL signaling pathway is thought to intersect by means of pVHL-mediated regulation of HIF function. HIF stabilization through hypoxia or loss of VHL function results in overexpression of c-MET and forms a synergistic effect in inducing invasion.

• #24 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Renal cell carcinoma (RCC) is a prevalent form of kidney cancer that arises from the cells lining the small tubes within the kidney. It stands as the predominant type of kidney cancer among adults, constituting approximately 95% of all cases. In more than 50% of patients diagnosed with ccRCC, the underlying cause can be attributed to a mutation in the Von Hippel-Lindau (VHL) gene. Ordinarily, the VHL gene functions as a tumor suppressor by regulating intracellular protein levels and hypoxia-inducible factors (HIF) 1 and 2. When the VHL gene is mutated, it leads to the accumulation of HIF, which is crucial for the survival of tumors like ccRCC in low oxygen conditions. This accumulation facilitates the survival of these tumors by promoting the production of growth factors such as platelet-derived growth factor (PDGF), vascular endothelial cell growth factor (VEGF), multidrug resistance pump, and erythropoietin. Through the expression of these HIF target genes and others, the tumor gains enhanced vascularity and develops resistance.

• #25 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. […] RCC is characterized by hypervascular nature and rely on increased production of growth factors, such as VEGF and PDGF-. Inactivation of VHL leads to deregulated stimulation of HIF-1 and HIF-2 genes, resulting in the activation of various oncogenes. However, it has been observed that a subgroup with only HIF-2 expression demonstrates primary resistance to antiangiogenic drugs. […] Lysosomal sequestration is a physiological process where hydrophobic weak base compounds accumulate within acidic lysosomes. This process is vital for the elimination of certain drugs and chemicals from the body, as well as for the regulation of cellular metabolism. Weak base compounds are lipophilic and can easily traverse cell membranes. However, when they reach the acidic lysosomal compartment, they undergo protonation due to their weak basic properties. As a result, they are unable to cross the lysosomal lipid membrane.

• #26 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. […] RCC is characterized by hypervascular nature and rely on increased production of growth factors, such as VEGF and PDGF-. Inactivation of VHL leads to deregulated stimulation of HIF-1 and HIF-2 genes, resulting in the activation of various oncogenes. However, it has been observed that a subgroup with only HIF-2 expression demonstrates primary resistance to antiangiogenic drugs. […] Lysosomal sequestration is a physiological process where hydrophobic weak base compounds accumulate within acidic lysosomes. This process is vital for the elimination of certain drugs and chemicals from the body, as well as for the regulation of cellular metabolism. Weak base compounds are lipophilic and can easily traverse cell membranes. However, when they reach the acidic lysosomal compartment, they undergo protonation due to their weak basic properties. As a result, they are unable to cross the lysosomal lipid membrane.

• #27 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. […] RCC is characterized by hypervascular nature and rely on increased production of growth factors, such as VEGF and PDGF-. Inactivation of VHL leads to deregulated stimulation of HIF-1 and HIF-2 genes, resulting in the activation of various oncogenes. However, it has been observed that a subgroup with only HIF-2 expression demonstrates primary resistance to antiangiogenic drugs. […] Lysosomal sequestration is a physiological process where hydrophobic weak base compounds accumulate within acidic lysosomes. This process is vital for the elimination of certain drugs and chemicals from the body, as well as for the regulation of cellular metabolism. Weak base compounds are lipophilic and can easily traverse cell membranes. However, when they reach the acidic lysosomal compartment, they undergo protonation due to their weak basic properties. As a result, they are unable to cross the lysosomal lipid membrane.

• #28 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Since many TKI are weak bases that can penetrate cell membranes, they become trapped in their protonated forms within the acidic lysosomal compartment, away from their intended targets. This leads to reduced drug efficacy and development of drug resistance. […] Pathway bypass mechanisms can contribute to drug resistance by activating alternative effector pathways that sustain oncogenic transcription and translational output. The tumor suppressor PTEN serves as a negative regulator of the PI3K/Akt/mTOR pathway. Mutations in PTEN function result in the constitutive activation of AKT/mTOR signaling downstream of the cellular targets of TKI. […] Mounting evidence indicates that the tumor microenvironment (TME) plays a pivotal role in the development of resistance to targeted therapies. This microenvironment encompasses tumor cells, the extracellular matrix (ECM), signaling molecules, and various types of stromal cells, including fibroblasts, vascular endothelial cells, pericytes, and immune cells.

• #29 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Since many TKI are weak bases that can penetrate cell membranes, they become trapped in their protonated forms within the acidic lysosomal compartment, away from their intended targets. This leads to reduced drug efficacy and development of drug resistance. […] Pathway bypass mechanisms can contribute to drug resistance by activating alternative effector pathways that sustain oncogenic transcription and translational output. The tumor suppressor PTEN serves as a negative regulator of the PI3K/Akt/mTOR pathway. Mutations in PTEN function result in the constitutive activation of AKT/mTOR signaling downstream of the cellular targets of TKI. […] Mounting evidence indicates that the tumor microenvironment (TME) plays a pivotal role in the development of resistance to targeted therapies. This microenvironment encompasses tumor cells, the extracellular matrix (ECM), signaling molecules, and various types of stromal cells, including fibroblasts, vascular endothelial cells, pericytes, and immune cells.

• #30 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Cells from both the innate and adaptive immune systems infiltrate the TME, forming an interconnected network that governs various aspects of tumor growth. […] The ability of MDSCs to suppress the immune system in cancer patients may serve as an indicator for predicting the effectiveness of ICI therapy. […] Overall, efforts are underway to overcome treatment resistance through ongoing research in various areas, including the identification of biomarkers and exploration of new pathways such as mTOR and the Ang/Tie-2 pathway. These areas hold promise for developing targeted therapies that can effectively address resistance in ccRCC.

• #31 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The results of clinical trials evaluating the efficiency of TKI pharmaceutical agents in nccRCC are controversial. […] The binding of two cell surface receptors of immune cells, programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), to their ligands on tumor cells results in inhibiting the cellular immune response. […] Therefore, the ICIs targeting PD-1/PD-L1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) are approved to treat RCCs. […] Given the highly invasive nature and poor outcomes of this disease, there is an urgent need to identify the molecular signature and therapeutic targets.

• #32 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. […] This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. […] Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regionsa feature increasingly recognized as a determinant of therapeutic resistance.

• #33 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. […] This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. […] Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regionsa feature increasingly recognized as a determinant of therapeutic resistance.

• #34 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  At the nexus of RCC pathogenesis lies metabolic reprogrammingan evolutionary hallmark enabling cancer cells to rewire nutrient acquisition and utilization, thereby sustaining proliferation amidst microenvironmental stressors. […] This metabolic plasticity transcends Otto Warburgs century-old observation of aerobic glycolysis (the Warburg effect), encompassing VHL/hypoxia-inducible factor (HIF)-driven pseudohypoxia, mechanistic target of rapamycin (mTOR)-mediated anabolic activation, and epigenetic regulation of nutrient transporters. […] ccRCC exemplifies this complexity: HIF-2 stabilization induces glycolysis via pyruvate dehydrogenase kinase (PDK)-mediated suppression of oxidative phosphorylation (OXPHOS), while simultaneously upregulating glutamine transporters to fuel reductive carboxylationa metabolic bypass sustaining lipid biosynthesis under hypoxia.

• #35 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  At the nexus of RCC pathogenesis lies metabolic reprogrammingan evolutionary hallmark enabling cancer cells to rewire nutrient acquisition and utilization, thereby sustaining proliferation amidst microenvironmental stressors. […] This metabolic plasticity transcends Otto Warburgs century-old observation of aerobic glycolysis (the Warburg effect), encompassing VHL/hypoxia-inducible factor (HIF)-driven pseudohypoxia, mechanistic target of rapamycin (mTOR)-mediated anabolic activation, and epigenetic regulation of nutrient transporters. […] ccRCC exemplifies this complexity: HIF-2 stabilization induces glycolysis via pyruvate dehydrogenase kinase (PDK)-mediated suppression of oxidative phosphorylation (OXPHOS), while simultaneously upregulating glutamine transporters to fuel reductive carboxylationa metabolic bypass sustaining lipid biosynthesis under hypoxia.

• #36 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  These adaptations generate an immunosuppressive tumor microenvironment (TME) through lactate accumulation (extracellular pH 6.5), kynurenine-mediated T cell exhaustion, and adenosine-driven myeloid suppression. […] Metabolic reprogramming plays a pivotal role in the development of renal cell carcinoma and its resistance to immune responses. […] Metabolic reprogramming holds promise as a therapeutic target for treating renal cell carcinoma. […] Metabolic reprogramming is one of the important mechanisms in the occurrence and development of tumors, which can regulate the biological behaviors such as growth and metastasis of malignant tumor cells, thereby affecting the development and therapeutic effects of tumors. […] Metabolic reprogramming stands as a defining feature of cancer pathogenesis, enabling malignant cells to circumvent microenvironmental constraints through dynamic adjustments in nutrient acquisition and utilization.

• #37 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  These adaptations generate an immunosuppressive tumor microenvironment (TME) through lactate accumulation (extracellular pH 6.5), kynurenine-mediated T cell exhaustion, and adenosine-driven myeloid suppression. […] Metabolic reprogramming plays a pivotal role in the development of renal cell carcinoma and its resistance to immune responses. […] Metabolic reprogramming holds promise as a therapeutic target for treating renal cell carcinoma. […] Metabolic reprogramming is one of the important mechanisms in the occurrence and development of tumors, which can regulate the biological behaviors such as growth and metastasis of malignant tumor cells, thereby affecting the development and therapeutic effects of tumors. […] Metabolic reprogramming stands as a defining feature of cancer pathogenesis, enabling malignant cells to circumvent microenvironmental constraints through dynamic adjustments in nutrient acquisition and utilization.

• #38 Research progress on the correlation between obesity and the occurrence and development of kidney cancer: a narrative review – Kang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/92315/html

  Obesity is an important risk factor for the onset of kidney cancer, and the mechanism of obesity leading to the occurrence and development of kidney cancer has been further studied and confirmed in the past decade. […] The latest evidence suggests that obesity is an important risk factor for the development of kidney cancer. Perirenal fat plays an important role in promoting kidney cancer progression and prognosis. […] The underlying mechanisms associated with obesity in promoting the occurrence and development of kidney cancer mainly include: abnormal expression of adipocytokines, abnormal lipid metabolism, abnormalities in the insulin-like growth factor-I (IGF-I) axis and hyperinsulinemia/insulin resistance, hypoxia and inflammation. […] Although the mechanism by which obesity leads to the development of kidney cancer has not been fully elucidated, the latest research highlights the role of obesity-related factors in cancer.

• #39 Research progress on the correlation between obesity and the occurrence and development of kidney cancer: a narrative review – Kang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/92315/html

  Obesity is an important risk factor for the onset of kidney cancer, and the mechanism of obesity leading to the occurrence and development of kidney cancer has been further studied and confirmed in the past decade. […] The latest evidence suggests that obesity is an important risk factor for the development of kidney cancer. Perirenal fat plays an important role in promoting kidney cancer progression and prognosis. […] The underlying mechanisms associated with obesity in promoting the occurrence and development of kidney cancer mainly include: abnormal expression of adipocytokines, abnormal lipid metabolism, abnormalities in the insulin-like growth factor-I (IGF-I) axis and hyperinsulinemia/insulin resistance, hypoxia and inflammation. […] Although the mechanism by which obesity leads to the development of kidney cancer has not been fully elucidated, the latest research highlights the role of obesity-related factors in cancer.

• #40 Research progress on the correlation between obesity and the occurrence and development of kidney cancer: a narrative review – Kang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/92315/html

  Excess body fat is associated with metabolic and endocrine abnormalities and can stimulate the occurrence and progression of obesity-related cancers. […] The physiological state of perirenal fat may have carcinogenic effects and affect the progression of kidney tumors. […] The interaction between insulin and the IGF system, which includes IGF-1, IGF-2 and its receptors (IGF-1R and IGF-2R), and six types of IGF-binding proteins (IGFBPs), appears to be critical to the development and progression of RCC. […] Hypoxia is a hallmark of solid tumors, and the effects of obesity on adipose tissue vascular function and oxygen supply have been well studied. […] Chronic inflammation has been shown to promote cancer progression. Obesity is associated with the secretion of a large number of pro-inflammatory cytokines that produce a low-grade chronic inflammatory state. […] The extent of radical nephrectomy requires free excision of the kidney and perirenal fat outside the perirenal fascia, so the completeness of perirenal fascial resection and the amount of residual perirenal fat may also have an important impact on the prognosis of patients with renal cancer.

• #41 Research progress on the correlation between obesity and the occurrence and development of kidney cancer: a narrative review – Kang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/92315/html

  Excess body fat is associated with metabolic and endocrine abnormalities and can stimulate the occurrence and progression of obesity-related cancers. […] The physiological state of perirenal fat may have carcinogenic effects and affect the progression of kidney tumors. […] The interaction between insulin and the IGF system, which includes IGF-1, IGF-2 and its receptors (IGF-1R and IGF-2R), and six types of IGF-binding proteins (IGFBPs), appears to be critical to the development and progression of RCC. […] Hypoxia is a hallmark of solid tumors, and the effects of obesity on adipose tissue vascular function and oxygen supply have been well studied. […] Chronic inflammation has been shown to promote cancer progression. Obesity is associated with the secretion of a large number of pro-inflammatory cytokines that produce a low-grade chronic inflammatory state. […] The extent of radical nephrectomy requires free excision of the kidney and perirenal fat outside the perirenal fascia, so the completeness of perirenal fascial resection and the amount of residual perirenal fat may also have an important impact on the prognosis of patients with renal cancer.

• #42 Investigating miRNA-related Pathways Contributing to Kidney Cancer Pathogenesis | Anticancer Research

  https://ar.iiarjournals.org/content/42/5/2355

  Renal cell carcinoma is one of the most common types of cancer worldwide. Understanding tumor pathogenesis is important in developing better treatment. Micro RNAs (miRNAs) are key players in controlling cancer behavior. Transcription factors (TFs) are potentially responsible for controlling miRNA expression and dysregulation in kidney cancer. The objective of this study was to better understand the TF-miRNA axis of interaction. […] It is well understood that the loss of the Von Hippel-Lindau tumor suppressor (VHL) gene contributes to the pathogenesis of RCC. […] Apart from the documented contribution of the VHL-hypoxia pathway to disease pathogenesis, other molecular factors that contribute to RCC pathogenesis have yet to be identified. […] An important level of eukaryotic molecular signaling involves short non-coding RNA sequences known as microRNAs (miRNAs, miRs). In an intricate manner, miRNAs are able to regulate the expression of their targets.

• #43 Investigating miRNA-related Pathways Contributing to Kidney Cancer Pathogenesis | Anticancer Research

  https://ar.iiarjournals.org/content/42/5/2355

  To identify RCC biomarkers and potential therapeutic targets, it is vital to understand the mechanisms that regulate miRNA expression and function. […] Recently, it has been shown that there is a TF-miRNA regulatory network that controls gene expression. Investigating this network in RCC can assist in better knowledge of how this contributes to renal carcinogenesis. […] Our results show that TFs have a particular level of transcriptional regulation of miRNA expression. However, the association between the two is more intricate than originally understood. Through publicly available databases, we identified significant complex interactions between TFs and miRNAs which have potentially important roles in the pathogenesis of RCC. […] In summary, we have shown that TFs represent an important mechanism for controlling miRNAs which contribute to the pathogenesis of RCC. With feed-forward and feedback mechanisms, the relationship between miRNAs and TFs is complex. The activation or repression of miRNAs by TFs can be used as potential therapeutic targets.

• #44 MicroRNAs: exploring a new dimension in the pathogenesis of kidney cancer | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-8-65

  Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. […] Recently, microRNAs (miRNAs) have been shown to be differentially expressed in RCC and their role in RCC pathogenesis is emerging. […] The VHL protein, which is defective in the majority of patients with RCC, plays a well characterized role in the pathogenesis of kidney cancer. […] Evidence of the involvement of miRNAs in RCC pathogenesis is emerging. Recent studies have documented miRNA dysregulation in RCC compared to normal kidney tissue. […] Some miRNAs have been shown to have an oncogenic effect on RCC. […] The current study by Neal et al. showed that miRNA expression can be VHL-dependant. […] miRNAs can directly control VHL, HIF, vascular endothelial growth factor receptor (VEGFR) and other key molecules in RCC pathogenesis. […] Current evidence shows that miRNAs will have a significant impact on our understanding of the pathogenesis of RCC. […] More studies are required in order to accurately identify the mechanisms by which miRNAs affect RCC.

• #45 Role of Autophagy in Renal Cancer

  https://www.jcancer.org/v10p2501.htm

  Autophagy is a highly conserved catabolic process with critical functions in maintenance of cellular homeostasis under normal growth conditions and in preservation of cell viability under stress. […] In recent years, it has been well demonstrated that autophagy may have relation with renal cell carcinoma (RCC). This review focuses on the research progress in relation between autophagy and RCC and the pharmacologic manipulation of autophagy for RCC treatment. […] However, the role of autophagy in the pathogenesis of renal cancer and the exact mechanism of its action are not clear. […] It has been reported that autophagy is a potential cell survival mechanism in metastatic RCC cells and autophagy inhibition could create synergistic cytotoxicity when combined with mTOR inhibitors in ccRCC.

• #46 Role of Autophagy in Renal Cancer

  https://www.jcancer.org/v10p2501.htm

  Autophagy is a highly conserved catabolic process with critical functions in maintenance of cellular homeostasis under normal growth conditions and in preservation of cell viability under stress. […] In recent years, it has been well demonstrated that autophagy may have relation with renal cell carcinoma (RCC). This review focuses on the research progress in relation between autophagy and RCC and the pharmacologic manipulation of autophagy for RCC treatment. […] However, the role of autophagy in the pathogenesis of renal cancer and the exact mechanism of its action are not clear. […] It has been reported that autophagy is a potential cell survival mechanism in metastatic RCC cells and autophagy inhibition could create synergistic cytotoxicity when combined with mTOR inhibitors in ccRCC.

• #47 Role of Autophagy in Renal Cancer

  https://www.jcancer.org/v10p2501.htm

  This led us to speculate that the regulation and function of autophagy is likely connected to maintenance of homeostasis of renal cancer cells, disease pathogenesis, and targeting therapy resistance. […] Exploring the delicate mechanisms and regulation of autophagy in renal cancer may lead to optimization in therapeutic strategies. […] The continuously activated PI3K/AKT/mTOR signaling axis is a typical survival mechanism for human tumor cells. […] Activation of the PI3K/AKT/mTOR axis not only inhibits autophagy but also promotes protein translation and cell proliferation. […] The tumor suppressor p53 is an important checkpoint protein in mammalian cells. […] In recent years, two large sample clinical studies have found the overexpression of p53 in renal cell carcinoma tissues suggesting that p53 is involved in the development of renal cell carcinoma (RCC).

• #48 Role of Autophagy in Renal Cancer

  https://www.jcancer.org/v10p2501.htm

  This led us to speculate that the regulation and function of autophagy is likely connected to maintenance of homeostasis of renal cancer cells, disease pathogenesis, and targeting therapy resistance. […] Exploring the delicate mechanisms and regulation of autophagy in renal cancer may lead to optimization in therapeutic strategies. […] The continuously activated PI3K/AKT/mTOR signaling axis is a typical survival mechanism for human tumor cells. […] Activation of the PI3K/AKT/mTOR axis not only inhibits autophagy but also promotes protein translation and cell proliferation. […] The tumor suppressor p53 is an important checkpoint protein in mammalian cells. […] In recent years, two large sample clinical studies have found the overexpression of p53 in renal cell carcinoma tissues suggesting that p53 is involved in the development of renal cell carcinoma (RCC).

• #49 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  Renal cell carcinomas (RCCs) account for approximately 85% of all primary kidney tissue neoplasms. Overall, incidence rates in men are usually higher than in women. RCCs are a heterogeneous group of cancers related to different histological characteristics, time of development of metastatic disease, genetic drivers, mutational load, and response to currently available therapies. Renal tumors are classified into subtypes based on morphology, cell of origin, and pathological features, including cytoplasmic characteristics in clear-cell RCC (ccRCC; 80%) and chromophobe RCC (chRCC; 5%), architectural structure in papillary RCC (pRCC; 15%), anatomical origin (very rare collecting duct versus renal medullary carcinomas), oncocytic or cystic disease-associated RCCs (less than 1%), molecular pathognomonic alterations (microphthalmia transcription factor family translocation carcinomas and succinate dehydrogenase (SDH)-deficient renal carcinomas), or familial predisposition syndromes (hereditary leiomyomatosis and RCC syndrome-associated renal cancer).

• #50 Clear Cell Renal Cell Carcinoma Pathology: Definition, World Health Organization 2022 Classification (5th edition) of Renal Tumors, Epidemiology

  https://emedicine.medscape.com/article/1612043-overview

  Clear cell renal cell carcinoma (CCRCC) is a renal cortical tumor originating from the proximal tubular epithelium of the kidney as solitary unilateral lesions capable of metastasizing to the lungs, bones, regional lymph nodes, liver, adrenal glands, and brain. […] The main inherited disorder predisposing to development of CCRCC is von Hippel-Lindau (VHL) disease, which involves a germline mutation of the VHL gene (3p25.3) at chromosome 3. […] Recent studies highlight the involvement of VHL mutations in both familial and sporadic CCRCC tumorigenesis. […] Studies in patients with VHL disease have established the importance of genetic alterations involving chromosome 3p in the development of CCRCC, while subsequent research has shown that chromosome 3 or 3p is lost in 80-98% of sporadic CCRCCs.

• #51 Clear Cell Renal Cell Carcinoma Pathology: Definition, World Health Organization 2022 Classification (5th edition) of Renal Tumors, Epidemiology

  https://emedicine.medscape.com/article/1612043-overview

  Clear cell renal cell carcinoma (CCRCC) is a renal cortical tumor originating from the proximal tubular epithelium of the kidney as solitary unilateral lesions capable of metastasizing to the lungs, bones, regional lymph nodes, liver, adrenal glands, and brain. […] The main inherited disorder predisposing to development of CCRCC is von Hippel-Lindau (VHL) disease, which involves a germline mutation of the VHL gene (3p25.3) at chromosome 3. […] Recent studies highlight the involvement of VHL mutations in both familial and sporadic CCRCC tumorigenesis. […] Studies in patients with VHL disease have established the importance of genetic alterations involving chromosome 3p in the development of CCRCC, while subsequent research has shown that chromosome 3 or 3p is lost in 80-98% of sporadic CCRCCs.

• #52 Clear Cell Renal Cell Carcinoma Pathology: Definition, World Health Organization 2022 Classification (5th edition) of Renal Tumors, Epidemiology

  https://emedicine.medscape.com/article/1612043-overview

  Molecular studies have shown that CCRCC exhibits VHL gene inactivation usually caused by an intragenic mutation (less frequently, due to promoter hypermethylation of one allele), coupled with a chromosome 3p deletion that affects the second copy of the VHL gene. […] Loss of a functional VHL protein therefore leads to upregulation of HIF-1 and activation of its hypoxia-inducible target genes under normoxic rather than hypoxic conditions. […] Chromosome 3p deletions lead to the concurrent loss of key tumor suppressor genes, including PBRM1, SETD2, and BAP1, which are critical in tumorigenesis of CCRCC. […] In CCRCC, mutations in PBRM1, BAP1, and SETD2 have been reported in 40%, 14%, and 3% of cases, respectively.

• #53 Clear Cell Renal Cell Carcinoma Pathology: Definition, World Health Organization 2022 Classification (5th edition) of Renal Tumors, Epidemiology

  https://emedicine.medscape.com/article/1612043-overview

  Molecular studies have shown that CCRCC exhibits VHL gene inactivation usually caused by an intragenic mutation (less frequently, due to promoter hypermethylation of one allele), coupled with a chromosome 3p deletion that affects the second copy of the VHL gene. […] Loss of a functional VHL protein therefore leads to upregulation of HIF-1 and activation of its hypoxia-inducible target genes under normoxic rather than hypoxic conditions. […] Chromosome 3p deletions lead to the concurrent loss of key tumor suppressor genes, including PBRM1, SETD2, and BAP1, which are critical in tumorigenesis of CCRCC. […] In CCRCC, mutations in PBRM1, BAP1, and SETD2 have been reported in 40%, 14%, and 3% of cases, respectively.

• #54 Kidney Cancer Types | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/kidney/types

  Clear cell RCC has been studied the most because it is by far the most common kidney cancer. Most of the medicines we use to treat kidney cancer were developed to treat clear cell RCC. […] Papillary tumors make up 10 to 15 out of every 100 kidney tumors. There are different types of papillary tumors. The kinds studied the most are called type 1 and type 2 papillary RCC. […] Chromophobe tumors make up about 5 out of every 100 kidney tumors. In many people, theyre less aggressive. But they can spread just like other types of RCC. […] These are very rare and make up less than 1 out of every 100 kidney tumors. Theyre more common in younger adults. These are very aggressive cancers that spread from the kidney early. Once they have spread, they need different types of systemic therapy than other kidney cancers. […] Urothelial tumors affect the lining of the urinary tract, including the renal pelvis, ureters, bladder, and urethra. Urothelial (transitional cell) tumors are different from renal cortical tumors. They come from a different type of cell and behave more like bladder cancer.

• #55 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The prognosis of and efficacy of therapeutic options for nccRCCs are based on extrapolation methods from the clinical assessment used for more common ccRCC. In the following sections, we will describe the characteristic features of the major types of nccRCC, as well as the current cell-based and animal models for studying them. […] The major common non-clear cell subtypes of RCC include papillary, chRCC, collecting duct, medullary, translocation associated, and unclassified. […] The genetic basis of pRCC is mainly based on studies of the inherited form of the disease. Hereditary pRCC is a rare autosomal dominant disorder in which patients usually have multiple renal tumors and are at risk for developing type 1 papillary RCC. […] Type 1 pRCC is characterized by mesenchymal to epithelial transition (hepatocyte growth factor receptor, MET) proto-oncogene alterations or variations on chromosome 7, and type 2 pRCC has alterations in CDKN2A, SETD2, BAP1, PBRM1, FH, NF2, TFE3, NFE2L2, and ARE genes.

• #56 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The prognosis of and efficacy of therapeutic options for nccRCCs are based on extrapolation methods from the clinical assessment used for more common ccRCC. In the following sections, we will describe the characteristic features of the major types of nccRCC, as well as the current cell-based and animal models for studying them. […] The major common non-clear cell subtypes of RCC include papillary, chRCC, collecting duct, medullary, translocation associated, and unclassified. […] The genetic basis of pRCC is mainly based on studies of the inherited form of the disease. Hereditary pRCC is a rare autosomal dominant disorder in which patients usually have multiple renal tumors and are at risk for developing type 1 papillary RCC. […] Type 1 pRCC is characterized by mesenchymal to epithelial transition (hepatocyte growth factor receptor, MET) proto-oncogene alterations or variations on chromosome 7, and type 2 pRCC has alterations in CDKN2A, SETD2, BAP1, PBRM1, FH, NF2, TFE3, NFE2L2, and ARE genes.

• #57 Kidney Cancer Types | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/kidney/types

  Clear cell RCC has been studied the most because it is by far the most common kidney cancer. Most of the medicines we use to treat kidney cancer were developed to treat clear cell RCC. […] Papillary tumors make up 10 to 15 out of every 100 kidney tumors. There are different types of papillary tumors. The kinds studied the most are called type 1 and type 2 papillary RCC. […] Chromophobe tumors make up about 5 out of every 100 kidney tumors. In many people, theyre less aggressive. But they can spread just like other types of RCC. […] These are very rare and make up less than 1 out of every 100 kidney tumors. Theyre more common in younger adults. These are very aggressive cancers that spread from the kidney early. Once they have spread, they need different types of systemic therapy than other kidney cancers. […] Urothelial tumors affect the lining of the urinary tract, including the renal pelvis, ureters, bladder, and urethra. Urothelial (transitional cell) tumors are different from renal cortical tumors. They come from a different type of cell and behave more like bladder cancer.

• #58 Researchers Reveal Underlying Mechanisms of Rare Form of Kidney Cancer

  https://www.genengnews.com/topics/cancer/researchers-reveal-underlying-mechanisms-of-rare-form-of-kidney-cancer/

  Translocation renal cell carcinoma (tRCC) is a rare and aggressive form of kidney cancer. It was recognized as a type of kidney cancer in 2004 and accounts for about 5% of all renal cell carcinomas in adults and about 50% in children, yet the underlying mechanisms are not fully understood. […] The researchers discovered genetic alterations are rare in tRCC, except for the gene fusion from which it gets its name. Their findings suggest that tRCC may be responsive to treatment with immune checkpoint inhibitors. […] “tRCC is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions,” the researchers wrote. “Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases).”

• #59 Researchers Reveal Underlying Mechanisms of Rare Form of Kidney Cancer

  https://www.genengnews.com/topics/cancer/researchers-reveal-underlying-mechanisms-of-rare-form-of-kidney-cancer/

  Translocation renal cell carcinoma (tRCC) is a rare and aggressive form of kidney cancer. It was recognized as a type of kidney cancer in 2004 and accounts for about 5% of all renal cell carcinomas in adults and about 50% in children, yet the underlying mechanisms are not fully understood. […] The researchers discovered genetic alterations are rare in tRCC, except for the gene fusion from which it gets its name. Their findings suggest that tRCC may be responsive to treatment with immune checkpoint inhibitors. […] “tRCC is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions,” the researchers wrote. “Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases).”

• #60 2023 Kidney Cancer Highlight – A Novel Mechanism of Pathogenesis for Renal Medullary Carcinoma, Kidney Cancer Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/kcrp/research_highlights/23Msaouel_highlight

  Renal Medullary Carcinoma (RMC), a rare and aggressive type of kidney cancer with characteristic sickling (changing shape) of the red blood cells, is known to target young patients of African descent who carry sickle cell trait (St) or have sickle cell disease (SS). […] Several RMC patients have served in the U.S. Armed Forces, leading Dr. Msaouel to propose a model that could explain the pathogenesis of RMC and also explain how the kidneys respond to dehydration and other stressors experienced by Service Members. […] Dr. Msaouel was able to confirm his hypothesis that there is a strong association between exercise and renal hypoxia (decreased oxygen in the kidneys) in animals that carried the sickle cell trait. […] Further investigation revealed that mice with sickle cell trait had sickling of red blood cells, particularly in the renal inner medulla region of the kidneys.

• #61 2023 Kidney Cancer Highlight – A Novel Mechanism of Pathogenesis for Renal Medullary Carcinoma, Kidney Cancer Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/kcrp/research_highlights/23Msaouel_highlight

  Renal Medullary Carcinoma (RMC), a rare and aggressive type of kidney cancer with characteristic sickling (changing shape) of the red blood cells, is known to target young patients of African descent who carry sickle cell trait (St) or have sickle cell disease (SS). […] Several RMC patients have served in the U.S. Armed Forces, leading Dr. Msaouel to propose a model that could explain the pathogenesis of RMC and also explain how the kidneys respond to dehydration and other stressors experienced by Service Members. […] Dr. Msaouel was able to confirm his hypothesis that there is a strong association between exercise and renal hypoxia (decreased oxygen in the kidneys) in animals that carried the sickle cell trait. […] Further investigation revealed that mice with sickle cell trait had sickling of red blood cells, particularly in the renal inner medulla region of the kidneys.

• #62 2023 Kidney Cancer Highlight – A Novel Mechanism of Pathogenesis for Renal Medullary Carcinoma, Kidney Cancer Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/kcrp/research_highlights/23Msaouel_highlight

  Throughout the course of this research, increased hypoxia, including exercise-induced hypoxia, was found to be a substantial risk factor for RMC. […] Dr. Msaouel has reported data from mouse studies suggesting that high-intensity exercise is the first modifiable risk factor for RMC in individuals with sickle cell trait. […] Dr. Msaouel’s team reported that the reduced amount of blood flow to the right inner medulla, plus exercise-induced hypoxia increasing red blood cell sickling, led to mice incurring more regional microinfarcts in the right kidney than the left kidney. […] Clinical observations of patients with RMC were first compared to control patients. […] Dr. Msaouel’s team reported that results remained consistent, and they concluded that patients with sickle cell trait and sickle cell disease who engage in high-intensity activity were at a higher risk for RMC. […] Understanding the impact of exercise on those with sickle cell trait can possibly aid clinical practices in guiding these individuals to prevent RMC development.

• #63 2023 Kidney Cancer Highlight – A Novel Mechanism of Pathogenesis for Renal Medullary Carcinoma, Kidney Cancer Research Program, Congressionally Directed Medical Research Programs

  https://cdmrp.health.mil/kcrp/research_highlights/23Msaouel_highlight

  Throughout the course of this research, increased hypoxia, including exercise-induced hypoxia, was found to be a substantial risk factor for RMC. […] Dr. Msaouel has reported data from mouse studies suggesting that high-intensity exercise is the first modifiable risk factor for RMC in individuals with sickle cell trait. […] Dr. Msaouel’s team reported that the reduced amount of blood flow to the right inner medulla, plus exercise-induced hypoxia increasing red blood cell sickling, led to mice incurring more regional microinfarcts in the right kidney than the left kidney. […] Clinical observations of patients with RMC were first compared to control patients. […] Dr. Msaouel’s team reported that results remained consistent, and they concluded that patients with sickle cell trait and sickle cell disease who engage in high-intensity activity were at a higher risk for RMC. […] Understanding the impact of exercise on those with sickle cell trait can possibly aid clinical practices in guiding these individuals to prevent RMC development.

• #64 Renal cell carcinoma: a review of biology and pathophysiology

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5850086/

  The mammalian target of rapamycin (mTOR) is a protein kinase that is encoded by the MTOR gene. […] Everolimus and temsirolimus are mTOR inhibitors that are approved for the treatment of metastatic ccRCC. […] The cytotoxic component of the immune system plays a vital role in the recognition and subsequent rejection of several different types of cancer, including RCC. […] Several cancers, including ccRCC, express PD-L1 on their surface. […] The expression of PD-L1 allows these cancers to escape the cytotoxic immune response by inducing the apoptosis of cytotoxic T lymphocytes. […] A better understanding of the biology and pathogenesis of ccRCC has revolutionized the treatment approach. […] With a greater understanding of the pathogenesis of RCC, many therapeutic advances for metastatic disease have been introduced in the last decade.

• #65 Current understanding of the molecular mechanisms of kidney cancer: a primer for urologists

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2422955/

  Renal cell carcinoma (RCC), the fifth leading malignant condition for men and tenth for women, accounts for 3% of all malignancies in Canada. […] Understanding the molecular mechanisms involved in the pathogenesis of RCC has aided the development of molecular-targeted drugs for this disease. […] Significant developments in understanding the underlying genetic basis of RCC over the last 2 decades are attributed to intensive research about rare inherited renal cancer syndromes and the identification of the genes responsible for them. […] The study of renal cancer genes and their molecular mechanisms is of utmost importance because it may help identify targets for therapy that will improve survival. […] Inactivation or loss of the wild-type VHL allele results in failure to bind with HIF-1. Consequently, HIF-1 accumulates under normoxia, translocates from cytoplasm to nucleus and subsequently heterodimerizes with HIF-1 to enable binding to an HIF-responsive element and induce transcription of target genes leading to the production of GLUT-1 glucose transporter, platelet-derived growth factor, carbonic anhydrase genes CA IX and CA XII, vascular endothelial growth factor, and transforming growth factor, thereby contributing to renal carcinogenesis.

• #66 Renal Cell Carcinoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/281340-overview

  Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy. […] The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). […] Mutations of the VHL gene result in the accumulation of hypoxia-inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

• #67 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Cells from both the innate and adaptive immune systems infiltrate the TME, forming an interconnected network that governs various aspects of tumor growth. […] The ability of MDSCs to suppress the immune system in cancer patients may serve as an indicator for predicting the effectiveness of ICI therapy. […] Overall, efforts are underway to overcome treatment resistance through ongoing research in various areas, including the identification of biomarkers and exploration of new pathways such as mTOR and the Ang/Tie-2 pathway. These areas hold promise for developing targeted therapies that can effectively address resistance in ccRCC.

• #68 Non-Clear Cell Renal Cell Carcinoma: Molecular Pathogenesis, Innovative Modeling, and Targeted Therapeutic Approaches

  https://www.mdpi.com/2673-8937/2/4/42

  The results of clinical trials evaluating the efficiency of TKI pharmaceutical agents in nccRCC are controversial. […] The binding of two cell surface receptors of immune cells, programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), to their ligands on tumor cells results in inhibiting the cellular immune response. […] Therefore, the ICIs targeting PD-1/PD-L1 (nivolumab and pembrolizumab) and CTLA-4 (ipilimumab) are approved to treat RCCs. […] Given the highly invasive nature and poor outcomes of this disease, there is an urgent need to identify the molecular signature and therapeutic targets.

• #69 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  Key metabolic vulnerabilities such as the Warburg effect and altered lipid metabolism present potential intervention targets. […] Recent studies highlight the promise of targeting these pathways to slow RCC progression and improve outcomes, though challenges like tumor heterogeneity and metabolic flexibility hinder clinical application. […] Understanding the relationship between tumor metabolism and the immune system is vital for effectively combining metabolic inhibitors with therapies like immune checkpoint blockade. […] A personalized approach that considers patients unique metabolic profiles is essential. […] Advances in imaging, biomarkers, and selective metabolic inhibitors will enhance treatment strategies. […] Ultimately, while targeting metabolic pathways holds significant potential for RCC treatment, further research is necessary to address challenges and improve protocols, potentially transforming RCC management and patient survival rates.

• #70 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  Key metabolic vulnerabilities such as the Warburg effect and altered lipid metabolism present potential intervention targets. […] Recent studies highlight the promise of targeting these pathways to slow RCC progression and improve outcomes, though challenges like tumor heterogeneity and metabolic flexibility hinder clinical application. […] Understanding the relationship between tumor metabolism and the immune system is vital for effectively combining metabolic inhibitors with therapies like immune checkpoint blockade. […] A personalized approach that considers patients unique metabolic profiles is essential. […] Advances in imaging, biomarkers, and selective metabolic inhibitors will enhance treatment strategies. […] Ultimately, while targeting metabolic pathways holds significant potential for RCC treatment, further research is necessary to address challenges and improve protocols, potentially transforming RCC management and patient survival rates.

• #71 Renal Cell Cancer – Insights in Drug Resistance Mechanisms | Anticancer Research

  https://ar.iiarjournals.org/content/43/11/4781

  Cells from both the innate and adaptive immune systems infiltrate the TME, forming an interconnected network that governs various aspects of tumor growth. […] The ability of MDSCs to suppress the immune system in cancer patients may serve as an indicator for predicting the effectiveness of ICI therapy. […] Overall, efforts are underway to overcome treatment resistance through ongoing research in various areas, including the identification of biomarkers and exploration of new pathways such as mTOR and the Ang/Tie-2 pathway. These areas hold promise for developing targeted therapies that can effectively address resistance in ccRCC.

• #72 Researchers Reveal Underlying Mechanisms of Rare Form of Kidney Cancer

  https://www.genengnews.com/topics/cancer/researchers-reveal-underlying-mechanisms-of-rare-form-of-kidney-cancer/

  “Altogether, we demonstrate the power of an integrative clinico-genomic analysis to illuminate the molecular underpinnings and clinical features of tRCC,” the researchers wrote. “Our work inspires multiple hypotheses that can be pursued in future studies to further dissect the biology of this rare cancer. These data also lay the framework for the development and testing of mechanism-driven therapeutic regimens in tRCC.” […] “We think our findings regarding the potential of immunotherapy combinations could be immediately clinically actionable,” said lead author Ziad El Bakouny, MD, a resident in internal medicine at the Brigham. “Because this cancer is so rare, it is difficult to have clinical trials dedicated to it. Comprehensively studying its molecular and clinical features may help us develop a better roadmap for treatment.”

• #73 Genes Associated with Renal Cell Carcinoma Investigated – NCI

  https://dceg.cancer.gov/news-events/news/2024/genes-renal-cell-carcinoma

  Past research in DCEG identified 50 new genomic regions associated with renal cell carcinoma, the most common form of kidney cancer. […] To better understand renal cell carcinogenesis, researchers used transcriptome- and proteome-wide association studies to increase understanding of genes and proteins associated with renal cell carcinoma and identify potential therapeutic targets. […] Several identified genes previously connected to risk of other cancer types were linked to renal cell carcinoma for the first time in this study. […] In particular, a large fraction of the genes identified were found to be targets of key transcription factors (e.g., hypoxia induction), which have been known to play a key role in several cancers, including renal cell carcinoma. However, the exact mechanism of how these genes influence renal cell carcinoma risk needs further investigation.

• #74 The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma | Cell Death Discovery

  https://www.nature.com/articles/s41420-025-02479-9

  Key metabolic vulnerabilities such as the Warburg effect and altered lipid metabolism present potential intervention targets. […] Recent studies highlight the promise of targeting these pathways to slow RCC progression and improve outcomes, though challenges like tumor heterogeneity and metabolic flexibility hinder clinical application. […] Understanding the relationship between tumor metabolism and the immune system is vital for effectively combining metabolic inhibitors with therapies like immune checkpoint blockade. […] A personalized approach that considers patients unique metabolic profiles is essential. […] Advances in imaging, biomarkers, and selective metabolic inhibitors will enhance treatment strategies. […] Ultimately, while targeting metabolic pathways holds significant potential for RCC treatment, further research is necessary to address challenges and improve protocols, potentially transforming RCC management and patient survival rates.

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