Materiały źródłowe

• #1 Immunological Basis in the Pathogenesis and Treatment of Bladder Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4637163/

  The pathogenesis and transition of normal urothelium into bladder carcinoma are multifactorial processes. Chronic inflammation causes initiation and progression of the underlying pathophysiology of invasive and metastatic cancer. A dichotomy is observed in the role of immune cells in bladder cancer. While the immune response defends the host by suppressing neoplastic growth, several immune cells, including neutrophils, macrophages, and T-lymphocytes, promote tumor development and progression. […] The mechanisms underlying the formation of urothelial carcinoma are many and complex, the details of which are still not fully understood. Several mechanisms, however, have been elucidated. Two pathways are used to describe the development of bladder cancer, the invasive pathway and the noninvasive papillary pathway.

• #1

  https://link.springer.com/article/10.1007/s10147-008-0812-0

  Bladder tumors show widely differing histopathology and clinical behavior. This is reflected in the molecular genetic alterations they contain. Much information has accumulated on somatic genomic alterations in bladder tumors of all grades and stages and when this information is related to the common histopathological appearances, a model for the pathogenesis of two major groups of bladder tumors has emerged. This review summarizes the genetic alterations that have been reported in bladder cancer and relates these to the current two-pathway model for tumor development. The molecular pathogenesis of high-grade noninvasive papillary tumors and of T1 tumors is not yet clear and possibilities are discussed. […] Bakker AA, Wallerand H, Radvanyi F, et al. (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 63:81088112 […] van Rhijn BW, van der Kwast TH, Vis AN, et al. (2004) FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res 64:19111914.

• #1 Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity – White Rose Research Online

  https://eprints.whiterose.ac.uk/86541/

  Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. […] Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. […] This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.

• #1 Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity – International Labour Organization

  https://labordoc.ilo.org/discovery/fulldisplay/cdi_proquest_miscellaneous_1676353988/41ILO_INST:41ILO_V1

  Key Points Bladder cancer is the fifth most common cancer in men in Western countries (male:female ratio is 3:1), and tobacco smoking is a major risk factor. There are two major groups of patients with distinct prognosis and molecular features. […] This Review discusses recent advances in the molecular characterization of bladder cancer, which has provided insights into pathogenesis and subgroups of bladder cancers with different prognosis. […] Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.

• #1 Bladder cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/bladder-cancer/symptoms-causes/syc-20356104

  Bladder cancer develops when cells in the bladder begin to grow abnormally, forming a tumor in the bladder. […] Bladder cancer begins when cells in the bladder develop changes (mutations) in their DNA. A cell’s DNA contains instructions that tell the cell what to do. The changes tell the cell to multiply rapidly and to go on living when healthy cells would die. The abnormal cells form a tumor that can invade and destroy normal body tissue. In time, the abnormal cells can break away and spread (metastasize) through the body. […] Different types of cells in your bladder can become cancerous. The type of bladder cell where cancer begins determines the type of bladder cancer. Doctors use this information to determine which treatments may work best for you. […] Urothelial carcinoma, previously called transitional cell carcinoma, occurs in the cells that line the inside of the bladder.

• #1 Bladder cancer – Wikipedia

  https://en.wikipedia.org/wiki/Bladder_cancer

  Bladder cancer is caused by changes to the DNA of bladder cells that result in those cells growing uncontrollably. These changes can be random, or can be induced by exposure to toxic substances such as those from consuming tobacco. Genetic damage accumulates over many years, eventually disrupting the normal functioning of bladder cells and causing them to grow uncontrollably into a lump of cells called a tumor. Cancer cells accumulate further DNA changes as they multiply, which can allow the tumor to evade the immune system, resist regular cell death pathways, and eventually spread to distant body sites. The new tumors that form in various organs damage those organs, eventually causing the death of the affected person. […] Bladder tumors typically arise from the urothelium, the cell layer that lines the urine-storing part of the bladder. Parts of the urothelium can accumulate DNA mutations over years, making these areas more likely to give rise to tumors. This effect, called field cancerization, can allow several tumors to arise in the same area, or tumors to re-emerge from a given area after a first tumor was removed. Additionally, a cell that becomes cancerous can grow to give rise to several tumors nearby and recurrent tumors are often monoclonal (descended from the same cancerous cell).

• #1 Molecular Oncology of Bladder Cancer from Inception to Modern Perspective

  https://www.mdpi.com/2072-6694/14/11/2578

  Bladder cancer (BC) is a common cancer that causes high morbidity and mortality among affected patients. As a carcinogen-driven cancer, molecular oncology of BC has contributed to several fundamental concepts in cancer biology. Molecular insights into the divergent pathways for low- and high-grade BC development, heterogeneity in bladder tumors regarding recurrence and progression, genetic polymorphism, and the associated risk for developing BC among smokers, driver mutations, and molecular subtyping of muscle-invasive BC for prognostic predictions find commonality with other cancers and therefore, have advanced the field of molecular oncology. […] The disparate behaviors of low-grade tumors, which almost always are NMIBC, and high-grade tumors, which are invasive and become MIBC, have driven the experimental advances that led to several key concepts, not just in BC but also in cancer research in general. These include the cellular origin of low- and high-grade tumors, urothelial/BC stem cells, tumor heterogeneity, lineage plasticity, influence of tumor microenvironment, genetic landscaping and driver mutations, “omic-based” profiling (mainly transcriptomic), and the molecular subtypes.

• #1 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Chinese Journal of Cancer Research

  http://www.cjcrcn.org/article/html_9295.html

  The knowledge of cellular mechanisms in malignances of the bladder has grown exponentially. […] This article outlines tumor molecular pathology of bladder cancer with an emphasis on several promising candidate biomarkers that may soon make their transition to the realm of clinical management of bladder cancer. […] Urinary bladder cancer (BC) is a heterogeneous disease with diverse morphologic and clinical manifestations. […] However, well-validated prognostic molecular biomarkers that help clinicians to identify patients who need early aggressive management are currently lacking. […] Superficial UC is thought to be originated from benign urothelium through hyperplasia with only a small contribution (10-15%) to the pool of high-grade noninvasive and subsequently invasive UC. […] Most invasive tumors appear to be originated through progression from dysplasia to flat carcinoma in situ (CIS) and high-grade noninvasive UC in which genetic instability leads to the accumulation of genetic alterations promoting progression to muscle-invasive bladder cancer (MI-BC).

• #1 FGFR3 – a Central Player in Bladder Cancer Pathogenesis?

  https://ouci.dntb.gov.ua/en/works/7W0Re1a4/

  The identification of mutations in FGFR3 in bladder tumors in 1999 led to major interest in this receptor and during the subsequent 20 years much has been learnt about the mutational profiles found in bladder cancer, the phenotypes associated with these and the potential of this mutated protein as a target for therapy. […] Based on mutational and expression data, it is estimated that >80% of non-muscle-invasive bladder cancers (NMIBC) and ~40% of muscle-invasive bladder cancers (MIBC) have upregulated FGFR3 signalling, and these frequencies are likely to be even higher if alternative splicing of the receptor, expression of ligands and changes in regulatory mechanisms are taken into account. […] This review will summarise what is known about the effects of FGFR3 and its mutant forms in normal urothelium and bladder tumors, will suggest when and how this protein contributes to urothelial cancer pathogenesis and will highlight areas that may benefit from further study.

• #1 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Zhao – Chinese Journal of Cancer Research

  https://cjcr.amegroups.org/article/view/9295/9976

  Superficial and muscle-invasive urothelial carcinoma (UC) of the bladder display two distinct clinical phenotypes with regard to the biologic behavior and prognosis. […] In addition, molecular evidence supporting two divergent pathways of pathogenesis for superficial and invasive disease is accumulating. Superficial UC is thought to be originated from benign urothelium through hyperplasia with only a small contribution (1015%) to the pool of high-grade noninvasive and subsequently invasive UC. Most invasive tumors appear to be originated through progression from dysplasia to flat carcinoma in situ (CIS) and high-grade noninvasive UC in which genetic instability leads to the accumulation of genetic alterations promoting progression to muscle-invasive bladder cancer (MI-BC). […] Three primary genetic alterations have consistently been associated with the pathogenic pathway of superficial non-muscle-invasive bladder cancer (NMI-BC). These altered molecules include: Tyrosine kinase receptor, FGFR-3, H-RAS, and PI3KCA.

• #1 The role of microbiota in tumorigenesis, progression and treatment of bladder cancer

  https://www.oaepublish.com/articles/mrr.2023.47

  For decades, the urinary system was regarded as a sterile environment due to the absence of any bacterial growth in clinical standard urine cultures from healthy individuals. […] Increasing pieces of evidence suggest microbiota exists in tumor tissue and plays a crucial role in tumor microenvironment based on research in multiple cancer models. Current studies about microbiota and bladder cancer have preliminarily characterized the bladder cancer-related microbiota, but how the microbiota influences the biological behavior of bladder cancer remains unclarified. […] The microbiota inside tumor tissue is demonstrated to be tumor type-specific and may directly modulate tumorigenesis, progression, and response to cancer treatment by various mechanisms. […] The mechanisms of how microbiota promotes tumorigenesis can be concluded as epithelium barrier destruction, inflammation, induction of gene mutations, influence of intracellular signaling transduction pathways for pro- or antitumor effects, etc., based on advances in different cancers.

• #1 Invasion Mechanisms of Bladder Cancer: A Molecular Review – Journal of Urological Surgery

  https://jurolsurgery.org/articles/invasion-mechanisms-of-bladder-cancer-a-molecular-review/doi/jus.1070

  Bladder cancer (BC) is a very common cancer and it has high mortality rates, especially in late stages. […] We do not know which factors and molecular processes are effective in the invasion mechanism. In this review, we summarized possible invasion mechanisms of BC. […] Mechanism of the invasion/metastasis includes separation from the epithelial collective, degradation of the surrounding matrix, migration and invasion through the basement membrane, intravasation and survival in the circulation, extravasation at a secondary site, survival as micrometastasis, and, finally, growth into overt metastases. […] MIBC expresses molecular markers of a developmental process known as epithelial-mesenchymal transition (EMT). […] EMT process include specification of a cell, disruption of the BM, change in the cell shape, withdrawal from the epithelial sheet and differentiation to a mesenchymal cell.

• #1 Elevated matrix metalloproteinase‑9 expression may contribute to the pathogenesis of bladder cancer

  https://www.spandidos-publications.com/10.3892/ol.2016.4187

  Elevated matrix metalloproteinase9 expression may contribute to the pathogenesis of bladder cancer. The present study investigated the potential association between matrix metalloproteinase9 (MMP9) expression and the pathogenesis of bladder cancer. The expression rates and protein levels of MMP9 were significantly increased in bladder cancer patients compared with the healthy controls. […] The MMP9 protein levels in bladder cancer patients and healthy controls were significantly different between Asian and Caucasian patients, but not African patients. […] The present meta-analysis results markedly indicate that MMP9 expression is associated with clinicopathological features of bladder cancer, suggesting that MMP9 may be a useful biomarker in the diagnosis and clinical management of bladder cancer, and may be a valuable therapeutic target.

• #1 Update on the Mechanism of Action of Intravesical BCG Therapy to Treat Non-Muscle-Invasive Bladder Cancer

  https://www.imrpress.com/journal/fbl/29/8/10.31083/j.fbl2908295

  While more than four decades have elapsed since intravesical Bacillus Calmette-Guérin (BCG) was first used to manage non-muscle invasive bladder cancer (NMIBC), its precise mechanism of anti-tumor action remains incompletely understood. […] Besides the classic theory that BCG induces local (within the bladder) innate and adaptive immunity through interaction with multiple immune cells, three new concepts have emerged in the past few years that help explain the variable response to BCG therapy between patients. First, BCG has been found to directly interact and become internalized within cancer cells, inducing them to act as antigen-presenting cells (APCs) for T-cells while releasing multiple cytokines. Second, BCG has a direct cytotoxic effect on cancer cells by inducing apoptosis through caspase-dependent pathways, causing cell cycle arrest, releasing proteases from mitochondria, and inducing reactive oxygen species-mediated cell injury. Third, BCG can increase the expression of programmed death ligand 1 (PD-L1) on both cancer and infiltrating inflammatory cells to impair the cell-mediated immune response. Current data has shown that high-grade recurrence after BCG therapy is related to CD8+ T-cell anergy or ‘exhaustion’. High-field cancerization and subsequently higher neoantigen presentation to T-cells are also associated with this anergy. This may explain why BCG therapy stops working after a certain time in many patients. This review summarizes the detailed immunologic reactions associated with BCG therapy and the role of immune cell subsets in this process. Moreover, this improved mechanistic understanding suggests new strategies for enhancing the anti-tumor efficacy of BCG for future clinical benefit.

• #1 BCG in Bladder Cancer Immunotherapy

  https://www.mdpi.com/2072-6694/14/13/3073

  Bacillus Calmette–Guérin (BCG) is a live attenuated strain of Mycobacterium bovis that is primarily used as a vaccine against tuberculosis. In the past four decades, BCG has also been used for the treatment of non-muscle invasive bladder cancer (NMIBC). In patients with NMIBC, BCG reduces the risk of tumor recurrence and decreases the likelihood of progression to more invasive disease. Despite the long-term clinical experience with BCG, its mechanism of action is still being elucidated. Data from animal models and from human studies suggests that BCG activates both the innate and adaptive arms of the immune system eventually leading to tumor destruction. Herein, we review the current data regarding the mechanism of BCG and summarize the evidence for its clinical efficacy and recommended indications and clinical practice.

• #1 The mechanism of action of BCG therapy for bladder cancer—a current perspective | Nature Reviews Urology

  https://www.nature.com/articles/nrurol.2014.15

  Despite nearly four decades of clinical experience with Bacillus Calmette-Gurin (BCG) for bladder cancer, the mechanism of its therapeutic effect is still under investigation. […] Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. […] The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. […] Immune system cell subsets that have potential roles in BCG therapy include CD4+ and CD8+ lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. […] Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. […] Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

• #1 Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer: Overview of BCG Immunotherapy, Mechanism of Action of BCG, Contraindications to BCG

  https://emedicine.medscape.com/article/1950803-overview

  Bacillus Calmette-Gurin (BCG), a live attenuated strain of Mycobacterium bovis, is currently the only agent approved by the US Food and Drug Administration for primary therapy of carcinoma in situ (CIS; see image below) of the bladder. BCG therapy also reduces the risk of recurrence, and ongoing maintenance therapy with BCG reduces the risk of progression in patients with high-grade nonmuscle invasive bladder cancer (NMIBC). […] The mechanism of action of bacillus Calmette-Gurin (BCG) therapy is incompletely understood. Some early studies purported that an immune response against BCG surface antigens cross-reacted with putative bladder tumor antigens, and this was proposed as the mechanism for the therapeutic effect of BCG; however, multiple subsequent studies refute this claim. […] The most likely mechanism of action of BCG immunotherapy involves a combination of its direct effect on tumor cells along with the patients immune response to the therapy. These effects are summarized by Kawai et al into three categories: infection of cancer cells, induction of immune response, and antitumor effects.

• #1 NMIBC | MIBC | Mechanism of Action of CG0070 | CG Oncology

  https://cgoncology.com/science/

  Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action that selectively replicates in and lyses cancer cells while simultaneously amplifying the immune response against bladder tumors. […] Cretostimogene grenadenorepvec works in two important and complementary ways. First, it replicates inside the tumor’s cells causing tumor cell lysis and immunogenic cell death. Then, the rupture of the cancer cells can release tumor-derived antigens, along with GM-CSF, that can stimulate a systemic anti-tumor immune response that involves the body’s immune system. […] Cretostimogene grenadenorepvec is being investigated in a global Phase 3 trial (BOND-003) as a monotherapy for the treatment of BCG-unresponsive, Non-Muscle Invasive Bladder Cancer (NMIBC). Most patients with high-risk NMIBC (CIS with or without Ta/T1, Ta or T1) who do not respond to BCG intravesical therapy (standard of care).

• #1 Roger Li, MD, Provides In-Depth Description of CG0070 Mechanism of Action in Bladder Cancer

  https://www.cancernetwork.com/view/roger-li-md-provides-in-depth-description-of-cg0070-mechanism-of-action-in-bladder-cancer

  Roger Li, MD, spoke about the mechanism of action of CG0070 used in combination with pembrolizumab to treat patients with nonmuscle invasive bladder cancer who were unresponsive to bacillus Calmette-Guerin. […] The oncolytic virus is an adenovirus backbone, Ad5 [adenovirus type 5], that detects cancer cells with a defective RB protein. Because of the defective RB protein, there is an increase in the E2 factor in the cells, which binds to the promoters of the virus and elicits the viral replication. In addition to that, the viral backbone also contains a GM-CSF transgene. It secretes GM-CSF, and the thought is it would attract antigen-presenting cells to the tumor microenvironment. […] The reason why we wanted to combine it with an immune checkpoint [inhibitor] is we theorize that there is a synergism between the mechanism of action of the oncolytic virus and immune checkpoint [inhibitors]. The virus can attract the immune cells to the tumor microenvironment, they act against the cancer cells, attack them, [the cells] get exhausted, and in turn, can be reinvigorated by the immune checkpoint blockade. Indeed, thats what were seeing as the preliminary results of our clinical trial.

• #1 Society of Urologic Oncology – MECHANISM OF ACTION AND TRANSLATION TO THE CLINIC OF DETALIMOGENE VORAPLASMID (EG-70) – A NOVEL, INVESTIGATIONAL NON-VIRAL IMMUNOTHERAPY FOR NON-MUSCLE-INVASIVE BLADDER CANCER

  https://suo-abstracts.secure-platform.com/a/gallery/rounds/21/details/3602

  Detalimogene voraplasmid (formerly known as EG-70) is a novel, investigational, non-integrating, non-viral gene therapy that was specifically designed to elicit local stimulation of anti-tumor immune response in the bladder while mitigating the risk of systemic toxicities from immune stimulation. […] We now present preclinical data supporting the mechanism of action of detalimogene voraplasmid, which involves immune cell recruitment, tumor microenvironment remodeling and, ultimately, immune training on neoantigens and tumor clearance. […] Immune profiling revealed a profound remodeling of the tumor microenvironment from an immunosuppressive phenotype to a pro-inflammatory milieu supportive of tumor clearance. […] These preclinical findings demonstrate that detalimogene voraplasmid delivers genetically encoded immunostimulatory payloads locally to the bladder. The mechanism of action described preclinically has been translated into the clinic in the Phase 1 part of the LEGEND study, in which detalimogene voraplasmid treatment of patients with BCG-unresponsive NMIBC with CIS was generally well tolerated, with an overall complete response rate of 73%.

• #1 Role of tyrosine kinases in bladder cancer progression: an overview | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00625-7

  Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. […] Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies. […] This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis. […] Over the past decades, mutations in kinases have been shown to be engaged in bladder malignancies. […] Dysregulation of TKs by gain of function mutations or over expression occurs in various malignancies like BCa which accelerates tumor proliferation and progression.

• #1 Oral Fenbendazole for Cancer Therapy in Humans and Animals | Anticancer Research

  https://ar.iiarjournals.org/content/44/9/3725

  Fenbendazole exhibits several other mechanisms contributing to its anti-cancer effects, primarily by disrupting energy metabolism. […] Studies attribute the anti-cancer mechanisms of fenbendazole to increasing p53 activation, inhibiting the GLUT1 transporter and hexokinase, and reducing glucose uptake in cancer cells. […] Fenbendazole induces mitochondrial translocation of p53, indicating activation of the p53-p21 pathway, which inhibits GLUT transporter expression and prevents glucose uptake in cancer cells. […] Through p53 activation, fenbendazole is believed to impede hexokinase II (HKII), the first glycolytic pathway enzyme critical for cancer cell growth. […] Thus, through targeting GLUT1, HKII, and glycolysis, fenbendazole can lead to cancer cell starvation and reverse drug resistance, aiding cancer treatment.

• #1 The Medical Letter Home Page | The Medical Letter, Inc.

  https://secure.medicalletter.org/TML-article-1705e

  Nogapendekin alfa inbakicept is an IL15 receptor agonist that consists of nogapendekin alfa bound to inbakicept. Binding of the drug to its receptor causes proliferation and activation of natural killer (NK) and CD8+ killer T cells, which attack tumor cells. It also activates CD4+ T helper cells, which enhance proliferation of memory killer T cells. […] FDA approval of nogapendekin alfa inbakicept was based on the results of an unpublished single-arm trial (QUILT-3.032; summarized in the package insert) in 77 adults with BCG-unresponsive, high-risk NMIBC with carcinoma in situ with or without papillary tumors. All patients underwent transurethral resection of the tumor before receiving nogapendekin alfa inbakicept and BCG. A complete response was achieved in 62% of patients and 58% of responders had a duration of response 12 months.

• #2 Bladder Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536923/

  Bladder cancer, a prevalent malignancy affecting the urinary system, arises from the tissues of the bladder, a hollow organ responsible for storing urine. Urothelial carcinoma is the most frequent type, constituting over 90% of cases in industrialized nations. This type of cancer is notably common among older adults, with risk factors including smoking, chemical exposure, and chronic bladder inflammation. Presenting symptoms such as gross or microscopic hematuria, urinary frequency, and pelvic pain lead to its detection. […] Early diagnosis and treatment are crucial for improving outcomes, as bladder cancer can range from noninvasive forms, which are confined to the inner layers of the bladder, to invasive types that penetrate deeper and can spread to other parts of the body. Treatment primarily involves transurethral resection and intravesical chemotherapy instillations but may also include laser ablation, Bacillus Calmette-Guerin bladder treatments, radiation therapy, chemotherapy, or surgical removal of part or all of the bladder.

• #2 Bladder Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536923/

  Urothelial carcinoma develops via two distinct pathways. One relates primarily to papillary neoplasms, and the other to flat or sessile lesions. […] Non-muscle-invasive bladder cancers (NMIBC) are typically low-grade papillary tumors that usually arise from simple hyperplasia and/or minimal dysplasia. This category also includes carcinoma in situ (CIS), a high-grade but superficial cancer. […] NMIBCs are characterized by the following: Activating mutations of fibroblast growth factor receptor 3, Inactivating mutations of STAG2, Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, The loss of heterozygosity of chromosome 9, Telomerase reverse transcriptase. […] Low-grade papillary NMIBC can progress to a muscle-invading malignancy in about 10% of cases due to cyclin-dependent kinase inhibitor 2A loss.

• #2 Bladder cancer – Wikipedia

  https://en.wikipedia.org/wiki/Bladder_cancer

  Despite arising from the same tissue, NMIBC and MIBC develop along distinct pathways and bear distinct genetic mutations. Most NMIBC tumors start as low-grade papillary (finger-like, projecting into the bladder) tumors. Mutations in cell growth pathways are common. Most common are mutations that activate FGFR3 (present in up to 80% of NMIBC tumors). Mutations activating the growth pathway PI3K/AKT/mTOR pathway are also common, including mutations in PIK3CA (in around 30% of tumors) and ERBB2/ERBB3 (up to 15% of tumors), and loss of TSC1 (50% of tumors). Major regulators of chromatin (influences the expression of different genes) are inactivated in over 65% of NMIBC tumors. […] MIBC often starts with low-lying, flat, high-grade tumors, that quickly spread beyond the bladder. These tumors have more genetic mutations and chromosomal abnormalities overall, with mutations more frequent than in any cancer but lung cancer and melanoma. Mutations that inactivate the tumor suppressor genes TP53 and RB are common, as are mutations in CDH1 (involved in metastasis) and VEGFR2 (involved in cell growth and metastasis).

• #2 Bladder Cancer: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/438262-overview

  FGFR-3, Ras, and PIK3CA mutations occur with high frequency in noninvasive tumors, leading to upregulation of Akt and mitogen-activated protein kinase (MAPK). […] Loss of heterozygosity (LOH) on chromosome 9 is among the most frequent genetic alterations in bladder tumors and is considered an early event. […] Alterations in the TP53 gene are noted in approximately 60% of invasive bladder cancers. […] Additionally, alterations in retinoblastoma (Rb), PTEN, and p16 are common in high-grade invasive cancers. […] In advanced disease, multiple mechanisms may lead to tumor progression. These include those that promote proliferation, survival, invasion, and metastasis, as well as those that involve deficiencies in DNA damage repair and the finding of stemlike cells. […] In addition to tumor cell alterations, the microenvironment may promote tumor growth by paracrine influences, including vascular endothelial growth factor (VEGF) production and aberrant E-cadherin expression. […] Finally, a growing body of research indicates that epigenetic alterations may silence tumor suppressor genes and that they represent important events in tumor progression.

• #2 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Chinese Journal of Cancer Research

  http://www.cjcrcn.org/article/html_9295.html

  Three primary genetic alterations have consistently been associated with the pathogenic pathway of superficial non-muscle-invasive bladder cancer (NMI-BC). […] Alterations in the RAS-MAPK and PI3K-Akt pathways are in mainly the cause for abnormal cell growth in urothelial neoplasia. […] The pathogenic pathway for MI-BC primarily involves alterations in tumor suppressor genes responsible for cell cycle control, including p53, p16, and Rb. […] Numerous molecular factors are involved in determining UC phenotype, genotype, biological behavior, and clinical outcomes. […] A variety of molecular markers, such as cell cycle regulators, cell proliferation promoters, signal transduction factors, apoptosis modulators, extracellular matrix-modulating molecules, and angiogenesis regulators, have been found to be associated with tumor grade and staging, risk of recurrence, and progression.

• #2 Bladder Cancer: Imperatives for Personalized Medicine

  https://www.cancernetwork.com/view/bladder-cancer-imperatives-personalized-medicine

  Activating FGFR3 mutations are found in 80% of low-grade Ta lesions and are the most common genetic alteration in bladder cancer. FGFR3 mutations are also found in 75% of benign nondysplastic urothelial papillomas and are rarely associated with CIS and TP53 mutations. The most common FGFR3 mutations-S249C in exon 7 (67%) and S375C in exon 10 (20%)-result in ligand-independent receptor dimerization, while the exon 15 mutation (3%) in the kinase domain predicts constitutive activation via altered protein conformation. Papillary tumors with concomitant CIS are generally FGFR3 wild-type, with patterns of chromosomal changes and gene expression signatures that are different from those seen in FGFR3-mutated tumors. While it appears that for the most part FGFR3 mutations do not play a significant role in invasive progression, invasive and metastatic tumors that carry activating mutations paradoxically behave in a more aggressive fashion. Current molecular studies have also suggested that NMIBC lesions might be better categorized on the basis of their FGFR3 status than by traditional grade and stage, and that such a categorization might improve current prognostic models.

• #2 Role of tyrosine kinases in bladder cancer progression: an overview | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-020-00625-7

  Therefore, inhibiting signaling pathways of different tyrosine kinases using tyrosine-kinase inhibitors (TKIs) have been reported as efficient method of tumor targeted therapies. […] Since, tyrosine-kinases have essential roles in BCa progression, in present review we have summarized all of the studies which have been assessed the role of tyrosine-kinases in BCa patients in the world. […] The HER2 amplification was significantly increased in urothelial bladder tumors with lymph node metastasis compared with initial tumors. HER2 amplification was also significantly associated with poor prognosis. […] It has been observed that the HER2 and NFkB up regulations had a key role in tumor cells resistance against chemotherapy among a sample of MIBC patients. […] It has been shown that the majority of UCC cases had mutations in PIK3CA, FGFR3, HRAS, KRAS, BRAF, and AKT1 genes.

• #2 Immunological Basis in the Pathogenesis and Treatment of Bladder Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4637163/

  Cancer develops when hyperplastic urothelium begins to grow towards the lumen of the bladder. This is often the result of genetic alterations in several proto-oncogenes, including fibroblast growth factor receptor-3 (FGFR3) and Harvey rat sarcoma viral oncogene (HRAS). […] Many cell types promote the development, invasion, proliferation, and metastasis of bladder cancer. […] Epithelial plasticity, the ability of cells to switch between phenotypic states, plays an important role in the transformation of healthy urothelial tissue into malignant neoplasm. […] Inflammation results in the release of several pro-tumor cytokines and growth factors that support tumor angiogenesis, proliferation, and survival. […] Chronic inflammation has a serious effect in the development and metastasis of cancer.

• #2 The role of microbiota in tumorigenesis, progression and treatment of bladder cancer

  https://www.oaepublish.com/articles/mrr.2023.47

  Persistent damage from microbiota, disruption induced by inflammation, and continuous regeneration of bladder epithelial cells cause genomic instability and increase the possibility of gene mutation. […] Multiple hits and steps induced by microbiota may contribute to the initiation of bladder cancer. […] The role of microbiota in tumorigenesis, progression and treatment of bladder cancer. […] The tumor microenvironment is closely related to tumor cell proliferation, invasion, metastasis, and other biological behaviors. […] The application of BCG in the treatment of bladder cancer represents an example of microbe-mediated antitumor immunity, although the mechanism has not been fully elucidated. […] The intratumoral microbiota has been identified to influence multiple components of the tumor microenvironment, including tumor cells and immune cells, thus leading to boosting or control of tumor development.

• #2 Invasion Mechanisms of Bladder Cancer: A Molecular Review – Journal of Urological Surgery

  https://jurolsurgery.org/articles/invasion-mechanisms-of-bladder-cancer-a-molecular-review/doi/jus.1070

  Recently, there is also accumulating evidence that EMT/MET plays important roles in cancer progression, invasion and metastasis, resistance to the apoptosis, and refractory responses to chemotherapy. […] In this process, polarized epithelial cells progressively alter their junctional and polarity complexes to acquire morphological and biochemical characteristics typical of mesenchymal cells. […] Recently, there have been many studies about tumor-initiating cells (cancer stem cells) in the literature. […] According to the recent studies, EMT is strongly associated with aggressive BC behavior, such as recurrence, progression, and metastasis. […] In addition, EGFR and miR-200 family members have been found to be predictive of cisplatin-based chemo-responsiveness. […] The ability of GSLs and gangliosides to interact with various signal transducers, as well as with receptors for growth factors (GFs) or integrins, to define cell adhesion, motility, and growth were well established in many previous studies.

• #2 Elevated matrix metalloproteinase‑9 expression may contribute to the pathogenesis of bladder cancer

  https://www.spandidos-publications.com/10.3892/ol.2016.4187

  The present results revealed that the expression rates of MMP9 in bladder cancer patients were significantly increased compared with the expression rates in the healthy control individuals, suggesting that the MMP9 protein is associated with the pathogenesis of bladder cancer. […] The present findings are consistent with previous studies, which suggested that MMP9 plays a role in bladder cancer. […] The present study identified that the expression rates of MMP9 in bladder cancer patients was significantly increased compared with healthy control individuals. […] The present results suggest that the serum MMP9 level is an important molecular biomarker, which may identify the initiation and predict the progression of bladder cancer. […] In conclusion, the results of the present meta-analysis demonstrated that MMP9 is associated with the clinicopathological features of bladder cancer, suggesting that MMP9 may be used in combination with other tumor-specific markers, which may improve the sensitivity of diagnosis and treatment of bladder cancer.

• #2 Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity | Nature Reviews Cancer

  https://www.nature.com/articles/nrc3817

  This study suggests that deletion of p16 makes a critical contribution to progression of NMIBCs. Subsequent genome sequencing studies define a subgroup of MIBCs with this profile. […] This study was the first to identify oncogenic FGFR3 fusions in bladder cancer. Importantly, cell lines with FGFR3 fusions were those previously reported to show high sensitivity to FGFR-targeted agents. […] This genome-wide methylation study of normal urothelium and tumours of all grades and stages found distinct patterns of hypomethylation in NMIBCs and widespread promoter hypermethylation in invasive tumours.

• #2 BCG in Bladder Cancer Immunotherapy

  https://www.mdpi.com/2072-6694/14/13/3073

  The mechanism of BCG therapy of bladder cancer is still not completely understood. Many mechanisms have been proposed, including direct interaction of BCG with urothelial and bladder cancer cells, activation of an innate immune response, and initiation of BCG-specific and tumor-specific T cell immunity. It is likely that the mechanism of BCG requires a combination of several of these factors. […] Once it has been instilled into the bladder, the initial interaction between BCG and the recipient is contact between bacteria and the urothelium, including bladder cancer cells themselves. BCG can attach to urothelial cells, possibly facilitating downstream immune responses. The proposed mechanism of BCG’s attachment to the urothelium is through association of mycobacterial fibronectin attachment proteins (FAPs) to host fibronectin which, in turn, attaches to urothelial cells through integrin α5β1.

• #2 Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer: Overview of BCG Immunotherapy, Mechanism of Action of BCG, Contraindications to BCG

  https://emedicine.medscape.com/article/1950803-overview

  The infection of cancer cells is mediated by the glycoprotein fibronectin, which allows the internalization of BCG, breakdown of proteins, and cellular changes (antigen expression) that trigger the immune system. […] This immune response comprises specific cellular changes including surface receptor changes and release of various cytokines. Interferon (IFN) is considered to be an important part of this process and has been used in the past to determine appropriate response to treatment. […] The immune response crescendos to antitumor activity in which cells (eg, cytotoxic T lymphocytes, natural killer cells, neutrophils, and macrophages) recognize the cancer cells, target them for destruction, and subsequently decrease cancer burden. […] The overall response to BCG is limited if the patient is immunosuppressed.

• #2 Oral Fenbendazole for Cancer Therapy in Humans and Animals | Anticancer Research

  https://ar.iiarjournals.org/content/44/9/3725

  In addition to glycolysis inhibition, fenbendazole induces apoptosis in cancer cells. […] Fenbendazole also acts as a microtubule destabilizing agent. […] Fenbendazole induces cell cycle arrest in the G2/M phase and demonstrates tubulin destabilization activity at concentrations of 1 and 10 M, with more cell cycle arrest demonstrated at higher concentrations (10 M). […] Fenbendazole causes oxidative stress and activates the MEK3/6-p38MAPK pathway, inhibiting cancer cell proliferation and enhancing apoptosis. […] Fenbendazole’s disruptive effects on energy metabolism are fascinating areas of study that could lead to significant advancements in cancer treatment. […] By increasing p53 expression and impacting multiple cellular pathways that act on GLUT and HKII, fenbendazole down-regulates glucose uptake, causing cancer cell starvation and enhancing apoptosis.

• #3 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Chinese Journal of Cancer Research

  http://www.cjcrcn.org/article/html_9295.html

  Chromosome 9 alterations are the earliest genetic alterations in both of the described divergent pathways of BC development. […] Several additional structural/numerical somatic chromosomal alterations also contributes to BC. […] Recent studies have pointed out the potential prognostic value of evaluating the expression of receptor tyrosine kinases such as FGFR3, NRAS, HRAS, epidermal growth factor receptor (EGFR), and other ERB family members (HER2/neu and ERBB2) in superficial and muscle invasive BC disease. […] Previous studies have shown compelling evidence of frequent FGFR3 mutations in low grade bladder cancer. […] Mutations in TP53 which codes for the p53 tumor suppressor protein, is critical in BC. […] Missense mutations in TP53 lead to an altered protein that is resistant to degradation through the ubiquitin pathway and results in nuclear accumulation of p53.

• #3 Bladder cancer – Wikipedia

  https://en.wikipedia.org/wiki/Bladder_cancer

  Some genetic abnormalities are common to NMIBC and MIBC tumors. Around half of each have lost all or part of chromosome 9, which contains several regulators of tumor suppressor genes. Up to 80% of tumors have mutations in the gene TERT, which extends cells’ telomeres to allow for extended replication.

• #3 Bladder: Urothelial carcinomas

  https://atlasgeneticsoncology.org/solid-tumor/5001/bladder-urothelial-carcinomas

  Loss of heterozygosity (LOH) on chromosome 9 is almost never the characteristic first step in tumor development. LOH can be detected in up to 67% of markers tested. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss on chromosome 9 vary from patient to patient. To explain the type and extent of genetic damage in combination with the low stage and grade of these tumors, it was hypothesized that in bladder cancer pathogenesis an increased rate of mitotic recombination is acquired early in the tumorigenic process.

• #3 Bladder Cancer: Imperatives for Personalized Medicine

  https://www.cancernetwork.com/view/bladder-cancer-imperatives-personalized-medicine

  The early identification of HRAS mutations in bladder cancer is a historic landmark in cancer research. Mutations in RAS genes (HRAS, NRAS, and KRAS2) have been identified in UC with more variable and lesser frequency than FGFR3 mutations, and with no association with tumor grade or stage. RAS and FGFR3 mutations appear to be mutually exclusive in Ta lesions, a finding that supports observations that oncogenic effects of mutationally activated FGFR3 are mediated by the Ras signaling pathway and that constitutional activation of the receptor tyrosine kinaseRas signaling pathway is responsible for the genesis of an overwhelming majority of Ta lesions. RAS mutations are equally frequent in Ta and invasive subgroups, however, raising the possibility that a subset of invasive cancers may have evolved from a low-grade papillary lesion. Synchronous and metachronous multifocal Ta tumors share genetic alterations, indicating genomic stability and a clonal origin. Interestingly, Ta tumors with more complex genetic alterations can appear earlier than their clonal counterparts with shared but less complex alterations, a phenomenon that indicates growth-advantaged evolution in the former lesions.

• #3 Bladder Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536923/

  Muscle-invasive bladder cancer (MIBC) arises from flat dysplasia or carcinoma in situ and is characterized by the following: The lesions show TP53 mutations and loss of heterozygosity of chromosome 9. Invasive carcinoma can then acquire metastatic potential by gaining RB1 and PTEN loss, together with other alterations. Copy number alterations and genetic instability correlate with tumor progression and a poorer prognosis. Overall, NMIBC usually shows diploid or near-diploid karyotypes as compared to muscle invading. MIBC is usually aneuploid, with numerous chromosomal alterations. […] Results from recent studies have demonstrated 4 subtypes of NMIBC based on abnormal ribonucleic acid (RNA) expression analyses. These abnormal prognostic molecular subtypes involve early cell cycle abnormalities, chromosomal instability, stem cell-like disorders, and immune depletion problems. Of these, chromosomal instability, which involves p53 and deoxyribonucleic acid damage repair genes, as well as apolipoprotein messenger RNA-editing enzyme, catalytic polypeptide, appears to be the most significant, as it has the highest recurrence and progression rates.

• #3 Immunological Basis in the Pathogenesis and Treatment of Bladder Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4637163/

  The production of oxygen species in inflamed tissues has also been shown to promote the formation of mutations in cancer cells. […] The balance between the subsets of T lymphocytes is critical in maintaining normal homeostasis and the environment in tissues. In bladder carcinoma, this balance is in flux due to the effect of cytokines that drives the differentiation of Tregs to TH17 cells. […] Despite extensive research in bladder cancer, the underlying cellular and molecular mechanisms remain unclear.

• #3 Invasion Mechanisms of Bladder Cancer: A Molecular Review – Journal of Urological Surgery

  https://jurolsurgery.org/articles/invasion-mechanisms-of-bladder-cancer-a-molecular-review/doi/jus.1070

  Increased motile activity, increased rate of cell proliferation and removal of growth inhibiting cell-cell contacts are hallmarks of tumorigenesis. […] During embryonic development, down regulation of E-cadherin function initiates a complex program wherein epithelial cells adopt a fibroblast-like phenotype and display tissue invasive activity, a process called EMT. […] Repression of E-cadherin appears to play a major role in EMT of epithelial-derived cancer types. […] In recent researches reported that, in 3D environments, E-cadherin deficiency indeed led to a loss of intercellular adhesion and triggered tumor cell invasion by matrix MMP-2 and MMP-9 driven matrix degradation. […] The current MMPs are classified into six groups as collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs.

• #3 BCG in Bladder Cancer Immunotherapy

  https://www.mdpi.com/2072-6694/14/13/3073

  Internalized BCG can be identified within the urothelial cells of patients receiving intravesical BCG. In vitro, bladder cancer cell lines can internalize BCG via macropinocytosis, a non-specific mechanism for the uptake of large particles that depends on the activation of the serine/threonine kinase P21 activated kinase (Pak1) by certain tumor aberrations, including activating mutations of Ras and inactivating mutations of phosphatase and tensin homolog (PTEN). […] Bladder cancer cells that have internalized BCG secrete various immune-activating effectors, including interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α, hinting at a possible mechanism in which internalization of BCG by bladder cells leads to recruitment or activation of immune cells.

• #4 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Zhao – Chinese Journal of Cancer Research

  https://cjcr.amegroups.org/article/view/9295/9976

  Altered cell cycle control is a hallmark of BC driven by both aberrant signal transduction as well as key alterations in cell cycle molecules such as p53 and pRb. […] Mutations in TP53 which codes for the p53 tumor suppressor protein, is critical in BC. […] Missense mutations in TP53 lead to an altered protein that is resistant to degradation through the ubiquitin pathway and results in nuclear accumulation of p53. […] This allows dysregulating progression of the cell through the G1-S checkpoint and drives cancer development and progression through altered apoptosis, DNA repair and response to therapy. […] Early studies have showed that p53 expression is strongly correlated with stage, progression and mortality of BC. […] A synergistic prognostic role for combining p53 evaluation with other cell cycle control elements such as pRb, cyclin E1, p21, and p27 is emerging in both NMI-BC and MI-BC.

• #4 Bladder Cancer: Imperatives for Personalized Medicine

  https://www.cancernetwork.com/view/bladder-cancer-imperatives-personalized-medicine

  To date, the most compelling differences between low-grade noninvasive lesions and invasive, high-grade tumors are alterations in the p53 and Rb tumor suppressor pathways. Multiple TP53 mutations, overexpression of HDM2, loss of p21 expression, and stabilized p53 expression, all of which carry an adverse prognosis in non-mutated tumors, have been identified. LOH in RB1 has been identified in over 50% of invasive tumors, and together with p53 status, Rb expression has been demonstrated to have prognostic significance. Additionally, E2F3 transcription factor overexpression associated with a 6p22 amplicon occurs exclusively in about 10% of invasive tumors, along with a high proliferation index and loss of Rb or p16 expression. […] LOH at the PTEN locus on chromosome 10q, observed exclusively in invasive tumors, has implicated the PI3-kinase pathway in the progressive phenotype of UC. Other genes in the PI3-kinase pathway, including TSC1 and PIK3CA, are found in bladder tumors of all stages and grades, and the different roles of this pathway may therefore contribute to different phenotypes of disease.

• #4 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Chinese Journal of Cancer Research

  http://www.cjcrcn.org/article/html_9295.html

  This allows dysregulating progression of the cell through the G1-S checkpoint and drives cancer development and progression through altered apoptosis, DNA repair and response to therapy. […] More recently, Mitra and colleagues showed that a nine panel marker comprising Bax, caspase-3, apoptotic protease activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and E-cadherin and smoking intensity, these molecules had significantly greater accuracy in a multivariate model in predicting survival in 212 bladder cancer patients than routine clinicopathological factors alone. […] Global approaches as well as pathway specific approaches continue to provide an insight into the pathways involved in development and progression of BC. […] Aberrant DNA methylation and histone modification have been proved to play a role in regulating gene expression and may contribute to carcinogenesis.

• #4 Invasion Mechanisms of Bladder Cancer: A Molecular Review – Journal of Urological Surgery

  https://jurolsurgery.org/articles/invasion-mechanisms-of-bladder-cancer-a-molecular-review/doi/jus.1070

  MMPs are the main group of regulating proteinases in ECM. MMPs are responsible for the turnover and degradation of almost all ECM components (collagen, laminin, FN), non-ECM cell regulators, integrin, kinases, chemokines and cytokines. […] Angiogenesis is fundamental to tumor growth, invasion and metastasis. […] Elevated levels of VEGF expression have also been detected in urine samples from UCB patients and correlated with disease recurrence and progression. […] It is suggested that VEGF, in combination with other angiogenic factors such as angiogenin and MMPs, may serve as a biomarker for the diagnosis and prognosis of patients with UCB.

• #4 BCG in Bladder Cancer Immunotherapy

  https://www.mdpi.com/2072-6694/14/13/3073

  A few studies have suggested that bladder cancer cells could initiate an immune response by presenting antigen to CD4 T cells; however, the ability to effectively present antigen and activate CD4 T cells is generally limited to professional antigen presenting cells. […] Despite the in vitro data cited above, there is no conclusive in vivo data demonstrating that internalization of BCG by urothelial cells is required for the efficacy of BCG. […] Finally, BCG can exert direct cytotoxic effects on bladder cancer cells, inhibiting their growth and even killing them. However, this phenomenon has primarily been demonstrated in vitro using high ratios of BCG to bladder cancer cells. Whether this mechanism is relevant in vivo remains uncertain.

• #5 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Zhao – Chinese Journal of Cancer Research

  https://cjcr.amegroups.org/article/view/9295/9976

  Global approaches as well as pathway specific approaches continue to provide an insight into the pathways involved in development and progression of BC. […] Several studies have used these approaches to identify presence or absence of disease, validate different pathways involved in different stages and grades of BC and finally to predict prognosis in NMI-BC and MI-BC. […] The authors combined the gene expression analysis, whole-genome array comparative genomic hybridization analysis, and mutational analysis of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 to identify 2 intrinsic molecular signatures (MS1 and MS2). […] Integrating all of the data, they were able to identify a few pathways that are consistently dysregulated in BC, including the p53/RB tumor suppressor pathway and the PI3K/AKT/mTOR and the RTK/RAS pathways, that affect cell proliferation and survival and pathways that affect epigenetic changes, such as chromatin remodeling and histone modification. […] These latter pathways, which affect epigenetic pathways, were seen in 89% of bladder tumors, more than in any other cancer studied, suggesting that there may be many subtle epigenetic causes of urothelial neoplasia that are still poorly understood.

• #5 Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview – Chinese Journal of Cancer Research

  http://www.cjcrcn.org/article/html_9295.html

  Multiple groups have demonstrated that hypermethylation of RARB, RASSF1 and DAPK is linked to aggressiveness of BC. […] In summary, as our understanding of the complex molecular mechanisms involved in the BC development has came into a deeper focus, our approaches for diagnosis and management of BC is also progress.

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