Materiały źródłowe

• #1 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone. […] The principal problem arising from prostate cancer (PCa) is its propensity to metastasize. This tendency arises from specific molecular mechanisms and interactions that together lead to local invasion, extravasation and distal migration from the primary site, followed by endothelial attachment, transmigration and site-specific establishment of metastases at secondary sites. Basic knowledge related to this structured process has improved recently, but many of the key elements are still poorly understood.

• #2 Prostate cancer – Wikipedia

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

  Prostate cancer is caused by the accumulation of genetic mutations to the DNA of cells in the prostate. These mutations affect genes involved in cell growth, replication, cell death, and DNA damage repair. With these processes dysregulated, some cells replicate abnormally, forming a clump of cells called a tumor. As the tumor grows, its cells accumulate more mutations, allowing it to stimulate the growth of new blood vessels to support further growth. Eventually, a tumor can grow large enough to invade nearby organs such as the seminal vesicles or bladder. In advanced tumors, cells can develop the ability to detach from their original tissue site, and evade the immune system. These cells can spread through the lymphatic system to nearby lymph nodes, or through the bloodstream to the bone marrow and (more rarely) other body sites. At these new sites, the cancer cells disrupt normal body function and continue to grow. Metastases cause most of the discomfort associated with prostate cancer, and can eventually kill the affected person.

• #3 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  Local invasion is one of the fundamental early steps in metastasis, as without it tumour spread cannot occur. To develop invasive potential, the malignant cell must down-regulate its cell-cell and cell-matrix adhesive characteristics, become motile and acquire the ability to break down the extracellular matrix (ECM) using degradative enzymes. […] Once the malignant cell has reached the interstitium, it must enter the vascular or lymphatic circulation by breaching the endothelial barriers. From there, the cell must migrate via the blood or lymphatic circulation and arrest at a secondary endothelial site before binding to the endothelium, extravasating and transmigrating through the endothelial layer to reach the interstitium, where it proliferates and/or coalesces with other metastasized cells to form a micro-metastasis.

• #4 Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2024.5692?text=fulltext

  The incidence of prostate cancer (PCa) is increasing, making it one of the prevalent malignancies among men. Metastasis of PCa to the bones poses the greatest danger to patients, potentially resulting in treatment ineffectiveness and mortality. […] Research has indicated that the spread of PCa to the bones occurs through the participation of numerous molecules and their respective pathways. Gaining knowledge regarding the molecular processes involved in bone metastasis may result in the development of innovative and well-tolerated therapies, ultimately enhancing the quality of life and prognosis of patients. […] The present article provides the latest overview of the molecular mechanisms involved in the formation of bone metastatic tumors from PCa. […] PCa bone metastasis involves four stages: Colonization, dormancy, reactivation and reconstruction.

• #5 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  The binding process is complete within 30-60 min and transmigration within 24 h. Once the cell reaches the interstitium, it may remain dormant for an undefined period or it may coalesce with other cells and proliferate to form a metastatic colony. […] Integrins are essential for cell-matrix attachment. Integrin expression varies between tumours, but over-expression of 6 and 3 integrins have been associated with increased invasion. […] This may suggest the anchorage of the malignant cell to the basement membrane (BM) or the involvement of signalling pathways related to cell motility. […] Whatever the actual mechanism, integrins are fundamentally important in the binding and migration processes at metastatic sites, where they work together with enzymes that degrade the ECM and BM. […] In metastasis, this balance is vitally important both in endothelial barrier degradation and in the establishment of metastases within bone marrow stroma.

• #6 Pathways involved in natural progression of prostate cancer | RRU

  https://www.dovepress.com/mechanistic-insights-on-localized-to-metastatic-prostate-cancer-transi-peer-reviewed-fulltext-article-RRU

  In prostate cancer, mechanisms of cancer progression can be divided into the epithelial-to-mesenchymal transition (EMT), which defines epigenetic drivers for cancer cell migration and metastasis, and stromal interactions within the tumor microenvironment (TME) that allow for the survival of tumor cells in distant organs, such as the bone. […] Many patients with high-risk localized and advanced prostate cancer ultimately develop progression to mCRPC because of the eventual development of resistance to standard drugs that suppress testosterone production and target the androgen receptor signaling pathway. […] Given the potential role that EMT has in prostate cancer metastasis, the pathways involved in EMT induction, potentially, can be harnessed for drug targeting. […] The EMT transition has long been considered a paradigm of metastatic cancer progression and it refers to the transition of tumor cells with epithelial characteristics to cells with mesenchymal properties which facilitates mobility and metastases of the cancer cells within distant tissues and organs.

• #7 Pathways involved in natural progression of prostate cancer | RRU

  https://www.dovepress.com/mechanistic-insights-on-localized-to-metastatic-prostate-cancer-transi-peer-reviewed-fulltext-article-RRU

  In the setting of prostate cancer progression, EMT involves the upregulation of growth factors including transforming growth factor-beta (TGF-) and insulin-like growth factor (IGF-1), but also signaling pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) which are intertwined with androgen receptor (AR) signaling. […] Upregulation of these signaling pathways ultimately induces the expression of key transcription factors such as SNAI1/2, ZEB1, TWIST1, ETS, as well as tumor suppressor genes such as RB1, PTEN, and TP53 which all have a role in EMT regulation. […] Tumor progression occurs as cancer cells lose expression of epithelial markers, E-cadherin and -catenin, and acquire mesenchymal markers such as vimentin and N-cadherin, which leads to loss of cell-cell adhesion and increase in cell migration.

• #8 Therapy resistance in prostate cancer: mechanism, signaling and reversal strategies

  https://www.explorationpub.com/Journals/etat/Article/1002266

  The tumor microenvironment (TME) in PC is known for its diverse metabolic variations as a result of cancer cell heterogeneity, impacting proliferation and metastasis. […] Understanding the intricate mechanisms that drive tumor progression and therapeutic resistance is crucial for improving survival rates. […] The behaviour and biological properties of tumors are shaped by the interplay between the surrounding stromal cells and cancer epithelial cells within the TME. […] EMT enables localized primary tumor cells to develop invasive and migratory abilities, allowing them to spread and establish metastases in distant locations. […] The fact that androgenic regulation governs this phenotypic process highlights the need to study the TME to understand tumor formation, progression, and ultimately dissemination to other body parts.

• #9 Prostate Cancer and Metastasis: An Emphasis on EMT Mechanism | SpringerLink

  https://link.springer.com/chapter/10.1007/978-981-97-4612-5_5

  Metastasis from prostate cancer is still a major problem, affecting patients mortality rates and quality of life in general. Moreover, the presence of metastases is a direct determinant of the prognosis and clinical outcome of prostate cancer. Furthermore, metastasis thrives in the bone microenvironment. The progression of androgen-sensitive to castration-resistant and metastatic prostate cancer is a major clinical concern in prostate cancer treatment. Epithelial cells in prostate cancer can change their shape from cuboidal to spindle-shaped as the disease advances; this process is called epithelial-mesenchymal transition (EMT). The involvement of cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) in the progression of prostate cancer to castration-resistant and metastasis are being more and more highlighted by new findings. […] It is worth noting that metastatic disease development in prostate tumors may trigger the reactivation of a dormant embryonic pathway known as the epithelial-mesenchymal transition (EMT). A mesenchymal phenotype resembling cancer stem cells can be achieved by malignancies by EMT.

• #10 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  The Rho GTPases are similar to Ras in their structure and synthesis; their activation lies downstream of Ras and is therefore Ras-dependent. […] This Ras-Rho-mediated activity is thought to be important in cellular migration and metastasis in prostate and other cancers. […] The 'seed-soil’ hypothesis of Paget is exemplified by PCa, with its predilection for the red bone marrow of the axial skeleton. […] Once established at the secondary site, prostatic micro-metastases develop in the bone marrow space, often in close association with the bone surface, where the osteoblast-fibroblast microenvironment is disturbed locally. […] It is postulated that the first event in this metastatic developmental process is osteoclast-mediated bone resorption, leading to the release of stimulatory cytokines from the bone surface and inducing a cycle of resorption or tumour stimulation, but this hypothesis has not been proven definitively.

• #11 Metastatic Prostate Cancer: Treatment Options & Prognosis | ZERO Prostate Cancer

  https://zerocancer.org/stages-and-grades/metastatic-prostate-cancer

  Prostate cancer most commonly spreads to the bones, followed by the lymph nodes, lungs, liver, and brain. Regardless of where metastases form, the type of cancer remains the same. Prostate cancer that has metastasized to the bones is still prostate cancer, not bone cancer. […] More than 60% of men with advanced prostate cancer will eventually develop bone metastases. The bones most commonly affected are the spine, hips, and ribs. Once prostate cancer has spread to the bone it can become painful, but treatments like pain medications or radiation therapy to those areas can dramatically reduce pain and improve quality of life. […] Testosterone, the male sex hormone, fuels the growth of prostate cancer but it also is crucial to bone health. Treatment of prostate cancer with hormone therapy, including androgen deprivation therapy (ADT), blocks the production of testosterone which stops or slows the growth of the cancer. Without testosterone, bones can become weak and break more easily.

• #12 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Prostate cancer is a malignant tumor occurring in the prostate and is the most common tumor of the male genitourinary system which ranks second in the global incidence of male cancer, and fifth in mortality in the world. The probability of distant metastasis of prostate adenocarcinoma can be as high as 70%, and bone is the most common site of metastasis. Patients with bone metastasis often have complications such as bone metabolism disorder, bone pain, pathological fracture, spinal cord compression, and hypercalcemia, which significantly reduce their quality of life and overall survival. Bone metastases can cause several bone-related events, including pathological fractures, spinal cord compression, and pain, resulting in a poor prognosis for prostate cancer patients. […] At present, a large number of studies consider that the „seed and soil” theory is a better interpretation of the reason why prostate cancer is easy to metastasize in bone: the epithelial-mesenchymal transformation of prostate cancer cells into the blood circulation. Chemokines secreted by the bone microenvironment can attract prostate cancer cells to metastases to bone, and prostate cancer cells can further regulate the colonization environment by secreting some cytokines, making it more conducive to their survival and proliferation, and its interaction with the bone microenvironment changes the structure and function of bone. Bone metastasis of prostate cancer is completed in four steps, including colonization, dormancy, reactivation, and reconstruction. Studies on the mechanism of bone metastasis of prostate cancer have started several years ago, and currently focus on the interaction between cancer cells and the tumor microenvironment (TME).

• #13 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Dormant diffuse tumor cells can often develop into secondary tumors of bone, and dormant cells are often resistant to conventional chemotherapeutic drugs, preventing drug clearance from tumor cells. After bone metastasis of prostate cancer, dormant cancer cells congregate around osteoblasts and expresses high levels of tyrosine kinase receptors, which were involved in regulating the expression of transforming growth factor (TGF-) and its receptors. […] The activated tumor cells can enter the proliferative stage under the stimulation of various factors in the bone microenvironment. After metastasis to bone, the homeostasis between osteoblasts and osteoclasts is destroyed. In particular, the destruction of osteoblasts can form a „vicious cycle” to promote tumor cell growth, continuous osteoclast generation, and bone absorption. Bone metastasis in prostate cancer changes the balance between osteoclast absorption and osteoblast formation, and reconstructs the original bone structure and function, which is mainly manifested as osteoblastosis, accelerates the original bone injury at the end of metastasis, and forms the woven bone with random arrangement of collagen fibers. […] Multiple cytokines and pathways in the bone microenvironment of prostate cancer patients play a role in the colonization, dormancy, reactivation, and bone structure reconstruction associated with bone metastasis through complex mechanisms of action.

• #14 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  As the metastasis develops, an imbalance occurs in the regulated, coupled skeletal cycle of bone resorption and bone formation, resulting in accelerated and synchronous bone formation and resorption. […] Many stimulating factors have been identified with respect to osteoblastic metastases in PCa. These mechanisms have been clarified in recent years and point towards the importance of the endothelin axis. […] PECs produce ET-1, and its receptor, ETa, is present throughout the prostate gland. […] Although ET-1 is important, it is not the only osteoblast stimulator in PCa metastasis. Other factors include up-regulation of the Wnt pathway and production of cytokines, for example, bone morphogenetic protein, TGF-, IGF, vascular endothelial growth factor, platelet-derived growth factor and MDA-BF.

• #15 Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2024.5692?text=fulltext

  Numerous investigations have concentrated on the interplay between tumor cells and the tumor microenvironment (TME) when examining the mechanism of bone metastasis. […] Research has indicated that a range of cytokines play a role in the progression of metastasis of PCa to the bones. […] The emergence of drug resistance poses great difficulties. […] Hence, comprehending the molecular mechanism behind PCa bone metastasis would aid in the exploration of novel therapeutic approaches. […] The process by which PCa cells enter bone tissue through the blood circulation is defined as colonization. […] Chemokine and receptor interactions have been shown to have a notable role in the bone metastasis of PCa. […] Research has shown that, after knocking out androgen receptor (AR) signals in tumor-associated fibroblasts, the expression of chemokine ligand (CCL) 2 is significantly increased, and the migration ability of PCa cells is improved.

• #16 Research Progression in the Mechanism of Bone Metastasis and Bone-Targeted Drugs in Prostate Cancer

  https://auo.asmepress.com/articles/new-68-474.html

  Studies have shown that a variety of cytokines are involved in the process of bone metastasis in prostate cancer. Although bisphosphonate, denosumab, radium-223, and other drugs have been approved for the prevention and treatment of bone metastasis of prostate cancer, the relevant mechanisms and specific bone-targeted therapeutic drugs still need to be explored. […] The cytokines synthesized during bone matrix release and bone turnover promote the colonization of prostate cancer cells in the bone. Studies have demonstrated that chemokine and receptor interactions play an important role in bone metastasis of prostate cancer. The increase of chemokine ligand 12 (C-X-C motif chemokine ligand 12, CXCL12) in bone tissue is associated with tumor metastasis. CXCL12 binds to C-X-Cmotif chemokine receptor 4 (CXCR4) to promote the adhesion, invasion, and migration of prostate cancer cells.

• #17 Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2024.5692?text=fulltext

  PCa promotes the growth and survival of tumor cells in the bone environment through numerous molecular mechanisms, and recruit bystander dormant cells to participate in bone metastasis. […] The NF-B pathway plays a role in controlling various biological processes, such as inflammation and immune responses. […] Research has indicated that NF-B expression is upregulated during PCa progression, leading to an increased cell cycle progression and proliferation rate. […] The findings of this research indicate that FN14 facilitates the spread of PCa by activating the NF-B signaling pathway, implying that FN14 could potentially serve as a viable target for treating CRPC. […] The communication between cancer cells and bone tissue is also significant in the development of PCa metastasis to the bones, and extensive research has been conducted in this area.

• #18 Mechanism of Bone Metastasis in Prostate Cancer | Encyclopedia MDPI

  https://encyclopedia.pub/entry/24833

  NF-κB signaling pushes cancer metastasis in multiple directions, such as stimulating MMP expressions and regulating cell adhesion molecules, according to previous studies. […] After androgen deprivation therapy (ADT), some castration-sensitive PCa cells will transit into CRPC cells, which is the beginning of PCa metastasis. […] The third signaling pathway that is involved in PCa BM is the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade, which originates from the activation of the epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). […] Other minor mediators that are discovered to be associated with PCa BM include KDM8, miR-145, and CCCTC-binding factor (CTCF). […] The above research draws a large picture of the regulatory mechanism of BM in PCa cells.

• #19 The Pathogenesis of Prostate Cancer – Prostate Cancer – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571321/

  Prostate cancer involves the transformation of benign epithelial cells into their malignant phenotype. The most frequent process of cancer transformation in the prostate is called prostatic intraepithelial neoplasia (PIN). […] HGPIN has a high predictive value for predicting progression to adenocarcinoma. […] Studies have failed to establish a link between raised serum levels of androgens and prostate cancer. In fact, high androgen levels are linked to reduced risk of aggressive prostate cancer, whilst patients with low serum androgen levels have higher risk of prostate cancer recurrence and advanced pathology. […] Therefore, ARs are important clinically as they are seen as integral to the progression of disease in prostate cancer. […] Androgenic blockade, through LBP and 5-reductase antagonists, as well as HPG overstimulation via LH/GnRH analogues, leads to epithelial cell apoptosis and a transient response in preventing proliferation in prostate cancer treatment. Patients will inevitably develop CRPC and thus develop a more lethal form of prostate cancer. […] Studies have reported AR mutations play an important role in the malignant potential of CRPC and that androgen-independent prostate cancer cells exhibit high levels of AR genetic amplification.

• #20 Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02255-y

  Prostate cancer is a hormone-driven disease and its tumor cell growth highly relies on increased androgen receptor (AR) signaling. […] However, a subset of patients eventually progresses to castration-resistant disease. […] To date, various mechanisms of resistance have been identified including the development of AR-independent aggressive variant prostate cancer based on neuroendocrine transdifferentiation (NED). […] We believe that a deeper understanding of the complex molecular pathological mechanisms contributing to transdifferentiation will help to improve diagnostic procedures and develop effective treatment strategies. […] Indeed, in recent years, many scientists have made important contributions to unravel possible causes and mechanisms in the context of neuroendocrine transdifferentiation.

• #21 Hormone Therapy for Prostate Cancer Fact Sheet – NCI

  https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet

  Androgens are required for normal growth and function of the prostate, a gland in the male reproductive system that helps make semen. Androgens are also necessary for prostate cancers to grow. Androgens promote the growth of both normal and cancerous prostate cells by binding to and activating the androgen receptor, a protein that is expressed in prostate cells (1). Once activated, the androgen receptor stimulates the expression of specific genes that cause prostate cells to grow (2). […] Most prostate cancers eventually stop responding to hormone therapy and become castration (or castrate) resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory; however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.

• #22 Molecular biology of prostate cancer – UpToDate

  https://www.uptodate.com/contents/molecular-biology-of-prostate-cancer

  Metastatic prostate cancers can be lethal because they heterogeneously contain both androgen-dependent and androgen-independent malignant cells. […] For those cells that are androgen dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs) so that transcription of death-signaling genes is repressed. […] Androgen ablation therapies allow these genes to be expressed, triggering the biochemical cascade that results in apoptotic cell death, resulting in the eradication of the large fraction of androgen-dependent cancer cells. […] In contrast, androgen ablation does not induce apoptosis in androgen-independent cells; their eventual outgrowth is responsible for the lethality of advanced disease.

• #23 Prostate cancer – Wikipedia

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

  Metastatic prostate cancer tends to have more genetic mutations than localized disease. Many of these mutations are in genes that protect from DNA damage, such as p53 (mutated in 8% of localized tumors, more than 27% of metastatic ones) and RB1 (1% of localized tumors, more than 5% of metastatic ones). Similarly mutations in the DNA repair-related genes BRCA2 and ATM are rare in localized disease but found in at least 7% and 5% of metastatic disease cases respectively. […] The transition from castrate-sensitive to castrate-resistant prostate cancer is also accompanied by the acquisition of various gene mutations. In castrate-resistant disease, more than 70% of tumors have mutations in the androgen receptor signaling pathway amplifications and gain-of-function mutations in the receptor gene itself, amplification of its activators (for example, FOXA1), or inactivating mutations in its negative regulators (for example, ZBTB16 and NCOR1). These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease. Similarly, deletions of the tumor suppressor PTEN are harbored by 12-17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors. Less commonly, tumors have aberrant activation of the Wnt signaling pathway via disruption of members APC (9% of tumors) or CTNNB1 (4% of tumors); or dysregulation of the PI3K pathway via PI3KCA/PI3KCB mutations (6% of tumors) or AKT1 (2% of tumors).

• #24 Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02255-y

  However, the complexity of the diverse molecular pathways has not been captured completely, yet. […] This narrative review comprehensively highlights the individual steps of neuroendocrine transdifferentiation and makes an important contribution in bringing together the results found so far. […] Among others, advanced therapies targeting the androgen receptor axis have been considered causative for this development. […] Cell growth of AVPC often occurs completely independent of the androgen receptor signal transduction pathway and cells have mostly lost the typical cellular features of prostate adenocarcinoma. […] This complicates both diagnosis and treatment of this very aggressive disease. […] Clinically, AVPC (formerly known as anaplastic prostate cancer) has been suggested to be defined by at least one of the following characteristics, formulated by Aparicio et al.: 1) Histological evidence of small cell neuroendocrine prostate cancer (NEPC); 2) presence of exclusively visceral metastases; 3) predominant lytic bone metastases; 4) bulky lymphadenopathy or bulky high-grade tumor mass in the prostate/pelvis; 5) low PSA at initial presentation plus high volume bone metastases; 6) presence of neuroendocrine markers on histology or serum at initial diagnosis or progression, plus any of: elevated serum lactate dehydrogenase, malignant hypercalcemia and/or elevated serum carcinoembryonic antigen in the absence of other features; 7) short interval ( 6m) to androgen-independent progression following the initiation of hormonal therapy with or without the presence of neuroendocrine markers.

• #25 Mechanism of Prostate Cancer Initiation, Progression and Drug Resistance | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/25588/mechanism-of-prostate-cancer-initiation-progression-and-drug-resistance/magazine

  Primary prostate cancer (PCa) is dependent on androgen receptor signaling for survival and proliferation. Targeting the androgen receptor signaling axis has been standard clinical care. Next generation anti-androgen therapies (ADT) have had clinical success; however, the majority of prostate cancer cases will relapse with castration resistant prostate cancer (CRPC). Over the last decade, next generation sequencing efforts have painted a detailed picture of the highly heterogeneous genomic landscape of the different disease stages of prostate cancer (Localized PCa, Metastatic PCa, and CRPC). On a cellular level, three main mechanisms of ADT resistance are recognized. 1) Reactivation of AR-signaling, 2) Reactivation of the AR oncogenic cistrome by a related nuclear hormone receptor and 3) Lineage plasticity, dedifferentiation to a cellular phenotype that is independent of the drug-target (AR). However, how the plethora of mutations contribute to CRPC is poorly understood. Nor is it known how PCa tumor heterogeneity and microenvironment contributes to the onset of CRPC. Going forward it will be pivotal to gain insight in these complex processes to discover clinical solutions for CRPC.

• #26 Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02255-y

  The transdifferentiation from mCRPC to t-NEPC seems to be driven by epigenetic changes rather than genomic aberrations, though some point mutations and copy number aberrations might be indicative of AVPC. […] Therefore, changes in neuroendocrine markers are commonly accompanied by the deregulation of cellular signaling pathways involved in lineage-plasticity, stem-like behavior and epithelial-to-mesenchymal transition (EMT). […] This close connection of NED and plasticity has been illustrated by overexpression of the basal marker TROP2 and the EMT-inducer SNAIL in PCa cell models. […] Moreover, the deregulation of epigenetic factors such as chromatin modulators and histone modification writers and readers is necessary for the reprogramming of the cancer cells phenotype. […] Although the differences between t-NEPC and mCRPC seem to be more pronounced on the epigenetic and transcriptional level, there are characteristic genomic aberrations that have been found to be co-occurring or more frequent in t-NEPC and AVPC, in general.

• #27 Pathways involved in natural progression of prostate cancer | RRU

  https://www.dovepress.com/mechanistic-insights-on-localized-to-metastatic-prostate-cancer-transi-peer-reviewed-fulltext-article-RRU

  The molecular mechanisms by which bone metastases occur in prostate cancer are not fully known, but there is evidence that certain prostate tumor-derived factors promote changes in the bone microenvironment that allow for the colonization of circulating prostate cancer cells. […] In prostate cancer, the primary oncogenic drivers are chromosomal rearrangements and copy number alterations. […] Certain genomic alterations are specific to metastatic tumors in prostate cancer, including those involving the AR, CDK12, ZFHX3, RB1, GNAS, and OR5L1 genes. […] There appears to be a pattern of genomic changes that occur more often in mCRPC tumors, including mutations in SPOP, FOXA1, TP53, BRCA2, PTEN, and CHD1, as well. […] Mutations at this stage of prostate cancer appear to confer resistance to androgen deprivation and other systemic therapies such as AR-directed drugs.

• #28 The Pathogenesis of Prostate Cancer – Prostate Cancer – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK571321/

  Genetic analysis of CRPC tumors has identified that the gene for the protein phosphatase and tensin homolog (PTEN) is mutated in 20% of cases. PTEN is a tumor suppressor gene, it acts by negatively regulating the PI3K-AKT-mTOR pathway and halting the cell-cycle at the G1 stage therefore halting cellular proliferation. […] Loss of PTEN thus results in an increase in the PI3K-AKT-mTOR pathway as well as impairing normal AR regulation, resulting in increased cellular proliferation, AR expression and reduced apoptosis. […] Dysregulation in the programmed cell death mechanisms (apoptosis) is important in the pathogenesis of prostate cancer and is deemed a key driver in the exponential growth of tumor cells. […] In aggressive prostate cancer, Bcl-2 is upregulated, swinging the homeostatic balance firmly towards anti-apoptosis.

• #29 Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02255-y

  Genomic aberrations, especially those leading to the loss-of-function, of the tumor suppressor phosphatase and tensin homolog (PTEN) are amidst the most frequent findings in PCa. […] In metastatic disease, the abundance of aberrations in PTEN is significantly increased, especially in combination with deleterious variants in the well-known tumor suppressor genes RB1 and TP53. […] Although combined loss-of-function aberrations in TP53, RB1 and PTEN are found in mCRPC, the combination of genomic aberrations in at least two of these genes is indicative of AVPC. […] Studies with combinatorial knock-outs (KO) in mouse models and PCa cell lines have confirmed that single KOs are not sufficient to introduce an NE phenotype. […] In contrast, the combination but not the single KOs of TP53 and RB1 has induced the growth of an AR-low NE-like tumor in both models.

• #30 Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02255-y

  A triple KO model with PTEN loss has exhibited an even more aggressive growth with multiple metastases. […] In fact, the loss of AR rarely occurs due to genomic aberrations, but rather by epigenetic or posttranscriptional mechanisms. […] Taken together these results strongly support the notion of a transdifferentiation mechanism driving the emergence of t-NEPC in the majority of patients. […] An unanswered question remains whether this process involves a dedifferentiation step in which the adenocarcinoma cells first lose AR-specific gene expression and acquire basal or stem-like properties before proceeding to a second step in which they differentiate into NE cells, or whether the transdifferentiation arises directly skipping this putative intermediate stem-like cell stage.

• #31 Pathways involved in natural progression of prostate cancer | RRU

  https://www.dovepress.com/mechanistic-insights-on-localized-to-metastatic-prostate-cancer-transi-peer-reviewed-fulltext-article-RRU

  The process by which tumor cells promote the development of a permissive secondary microenvironment, or premetastatic niche, has generally been well demonstrated in many types of cancers, including prostate cancer. […] Prostate cancer cells and TME components may be involved in priming the bone microenvironment for metastases. […] ADT appears to influence the prostate stroma and contribute to the development of castration-resistance via CAF-mediated pathways. […] There has been an increasing body of evidence, in general, of stroma or TME-mediated treatment resistance. […] Understanding the pathways involved in the natural progression of prostate cancer provides the impetus for discovering unique mechanisms of hormone-resistance and metastases and developing targeted therapies that are highly efficacious and safe.

• #32 Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2024.5692?text=fulltext

  Secondary tumors of the bone are often derived from diffuse tumor cells that first enter a dormant state. […] The process of reactivation of dormant PCa cells in bone tissue involves a complex interplay of various molecular mechanisms. […] After PCa bone metastasis, the balance between osteoclast absorption and osteoblast formation is altered as the original bone structure and the function are reconstructed. […] The presence of PCa cells in the bone microenvironment triggers osteoclastogenesis, primarily through the release of factors such as RANKL and parathyroid hormone-related peptide. […] Understanding these mechanisms is critical, as they provide potential therapeutic targets to restore the balance between osteoclasts and osteoblasts, thereby addressing bone metastasis and improving patient outcomes in PCa.

• #33 Prostate cancer and metastasis initiating stem cells | Cell Research

  https://www.nature.com/articles/cr200850

  Androgen refractory prostate cancer metastasis is a major clinical challenge. […] Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. […] Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. […] Understanding the mechanistic basis that underlies the development of prostate cancer metastasis is fundamental to the development of treatment and preventive therapies. […] The identification of the cell of origin for metastatic prostate cancer must be a major goal of research in this area, in order to properly target therapy.

• #34 Prostate cancer and metastasis initiating stem cells | Cell Research

  https://www.nature.com/articles/cr200850

  The simplest definition of a CSC is that of a cell able to regenerate a tumor, i.e. a tumor-initiating cell. […] The expectation is that CSC’s will express overlapping markers with normal stem cells from the same tissue and that CSC’s will display high clonogenic activity in vitro. […] However, the most definitive property with respect to defining CSC’s is that of tumor initiation, and this is also the property that directly links CSC’s to metastatic colonizing cells. […] The direct demonstration of purified tumor-initiating cells from primary human prostate tumors has not been reported. […] Concerns exist for the immortalization model described above. […] The existence of abnormal karyotypes in telomerase-immortalized lines from non-cancerous derived epithelium underscores this problem.

• #35 Prostate cancer metastasis: roles of recruitment and reprogramming, cell signal network and three-dimensional growth characteristics – Ziaee – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/6577/html

  RANKL-expressing PCa cells can recruit and reprogram neighboring non-metastatic bystander or DCs via specifically activating transcription factors through the RANK-mediated downstream signaling network in vitro and in vivo. […] Understanding the underlying mechanisms of the recruitment and reprograming of DCs or CTCs by either experimental MICs or nMICs will provide significant insights into cancer evolution, progression, and metastasis with major implications for both basic biology and clinical medicine.

• #36 Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids

  https://escholarship.org/uc/item/6j91376f

  We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.

• #37 Molecular mechanisms of metastasis in prostate cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3735202/

  The molecular mechanisms of metastasis in PCa are complex and involve a number of specific steps and interrelated mechanisms. A more complete understanding of the molecular mechanisms controlling this process will help to develop novel therapies that may enable us to control this progressively fatal condition.

• #38 Molecular mechanisms and targeted therapy for the metastasis of prostate cancer to the bones (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2024.5692?text=fulltext

  The findings of this research therefore indicate that the presence of CDCP1 on EVs could potentially serve as a valuable indicator for identifying bone metastasis in individuals with PCa. […] Multiple molecules and related pathways are involved in PCa bone metastasis, and drugs targeting key molecules or pathways involved in bone metastasis are being discovered and validated in PCa.

• #39 Therapy resistance in prostate cancer: mechanism, signaling and reversal strategies

  https://www.explorationpub.com/Journals/etat/Article/1002266

  Chemotherapeutics currently used to treat CRPC include systemic therapies like cabazitaxel and docetaxel, as well as drugs such as abiraterone and enzalutamide that target AR activation either directly or indirectly. […] A considerable fraction of patients who are prescribed enzalutamide or abiraterone do not respond well to these drugs. […] Understanding the mechanisms behind docetaxel resistance is a frequent challenge caused by the irregular control of molecules involved in cell survival and death. […] The intricate nature of docetaxel resistance is influenced by these mechanisms. […] Understanding the mechanisms of multidrug resistance proteins (MDRP), like P-glycoprotein, is crucial in comprehending how these pumps work to expel drugs into the extracellular fluid. […] The resistance of NEPC to AR-targeted therapies can be attributed to several factors: Loss of AR signaling, Genomic alterations, Lineage plasticity, Alternative signaling pathways. […] Given the resistance of NEPC to conventional therapies, there is a need for alternative treatment strategies.

• #40 Metastatic Prostate Cancer Treatments | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/prostate/treatment/metastatic-prostate-cancer-treatments

  Metastatic prostate cancer is cancer that has spread to other parts of the body. Treatments for metastatic prostate cancer are called systemic therapies. These drugs move throughout your body to attack cancer cells wherever they are. Some systemic therapies can reduce the side effects of metastatic disease. Given together, these treatments help people with metastatic prostate cancer live longer, better lives. […] The 3 main types of systemic therapy are hormone therapy, chemotherapy, and immunotherapy. […] Hormone therapy slows or blocks prostate cancer cells from growing. Testosterone can cause prostate cancer cells to grow. Hormone therapy lowers the amount of testosterone your testicles make. It also blocks the action of testosterone and other male hormones. […] Chemotherapy is medication that kills cancer cells, given by mouth or intravenously (put into your vein). Chemotherapy for prostate cancer is an important treatment option when the disease has metastasized (spread).

• #41 Metastatic Prostate Cancer Treatments | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/types/prostate/treatment/metastatic-prostate-cancer-treatments

  Immunotherapy uses the power of the immune system to target cancer cells. […] The first immunotherapy treatment for people with advanced metastatic prostate cancer approved by the FDA was sipuleucel-T (Provenge). […] Another type of systemic therapy is called radiotherapeutics (or radiotherapies). […] A drug called radium-223 (Xofigo) is used to treat advanced prostate cancer with bone metastases (cancer that has spread to the bones). […] Newer radiation therapy treatments target prostate cancer cells instead of the surrounding bone. […] This treatment can prevent bone fractures and help you live longer, with a better quality of life.

• #42 Precision therapy for metastatic prostate cancer improves survival | Karolinska Institutet

  https://news.ki.se/precision-therapy-for-metastatic-prostate-cancer-improves-survival

  Men with metastatic castration-resistant prostate cancer should be treated primarily with second-generation hormone drugs, which offer better treatment response and longer life expectancy than chemotherapy. […] The effectiveness of ARPi varied depending on the patients genetic profile. […] Our study shows that it is possible to ensure that each patient receives the best treatment given the genetic profile of the tumour, says Henrik Grnberg, Professor of Cancer Epidemiology, MEB, Karolinska Institutet.

• #43 New Subtype of Treatment-Resistant Prostate Cancer – NCI

  https://www.cancer.gov/news-events/cancer-currents-blog/2017/prostate-cancer-resistant-new-subtype

  Researchers have identified what they believe is a new subtype of metastatic prostate cancer (stage IV) that does not rely on hormones to fuel its growth. […] According to new research published October 9 in Cancer Cell, some metastatic prostate cancers can grow without the help of any type of signaling driven by androgens such as testosterone. Instead, the tumor cells appear to be using a cell-signaling pathway called the fibroblast growth factor (FGF) pathway. […] These double-negative prostate cancer cells needed neither androgen receptor nor neuroendocrine signaling to survive. […] Instead, by using a series of experimental approaches, the researchers found that the double-negative prostate cancer cells rely on FGF and a signaling pathway activated by FGF, called the MAPK pathway, for their growth.

• #44 New Drug Hope for Prostate Cancer Patients | Prostate Cancer Foundation

  https://www.pcf.org/new-drug-hope-for-prostate-cancer-patients/

  Hormonetherapyisused to slow theprogressionof advancedprostate cancer, but cancersoftendevelop resistanceand continue to grow […] NXP800worksinan innovative way,bytargetingtheHeat Shock Factor1(HSF1)pathwaya master switch in cells thatis hijackedto support the growth of cancer cells, helping them withstand the stresses they come under as a tumour develops. […] The team atThe Institute of CancerResearch(ICR)studieddata from439advanced prostate cancersamples. […] They alsofound an association betweenpatients who hadhigherlevelsof theseproteinsandpoorer overall survival. […] The researchers attempted to block these heat shock proteins using the drug NXP800, which was discovered at the ICRinitsCentre for Cancer Drug Discovery. […] The team carried out mechanistic studies which confirmed that NXP800 blocks the activity of HSF1 in prostate cancer cells and reduces the levels of heat shock proteins.

• #45 Research uncovers alternate mechanism for producing key protein in metastatic prostate cancer

  https://www.dana-farber.org/newsroom/news-releases/2023/research-uncovers-alternate-mechanism-for-producing-key-protein-in-metastatic-prostate-cancer

  Like the better-known prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) is a biomarker that can tell physicians much about a patient’s metastatic prostate cancer. […] In a new study in the journal Nature Cancer, Dana-Farber Cancer Institute scientists shed new light on the mechanism that raises and lowers PSMA expression in prostate cancer cells. […] In the Nature Cancer study, researchers led by Dana-Farber’s Himisha Beltran, MD, and Martin Bakht, PhD, found that PSMA expression is lower in liver metastases than in other parts of the body, regardless of expression of the androgen receptor. […] Their search revealed that the HOXB13 protein as a key regulator of PSMA: when castration-resistant prostate cancers go without the AR, HOXB13 can control PSMA on its own. […] This and the discovery of an „epigenetic” mechanism for suppressing PSMA demonstrate that the system of PSMA control is more complex than once thought and that prostate cancer has multiple subtypes that may be optimally treated by specific targeted therapies.

• #46 Mechanism Uncovered for Production of Key Prostate Cancer Protein | Technology Networks

  https://www.technologynetworks.com/cancer-research/news/mechanism-uncovered-for-production-of-key-prostate-cancer-protein-371954

  Like the better-known prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) is a biomarker that can tell physicians much about a patient’s metastatic prostate cancer. […] In a new study in the journal Nature Cancer, Dana-Farber Cancer Institute scientists shed new light on the mechanism that raises and lowers PSMA expression in prostate cancer cells. […] It has long been known that the androgen receptor (AR) a structure that triggers cell growth in response to the hormone androgen controls the production of PSMA in prostate cancer cells. […] Their search revealed that the HOXB13 protein as a key regulator of PSMA: when castration-resistant prostate cancers go without the AR, HOXB13 can control PSMA on its own. […] This and the discovery of an „epigenetic” mechanism for suppressing PSMA demonstrate that the system of PSMA control is more complex than once thought and that prostate cancer has multiple subtypes that may be optimally treated by specific targeted therapies.

• #47 Metastatic Prostate Cancer: Treatment Options & Prognosis | ZERO Prostate Cancer

  https://zerocancer.org/stages-and-grades/metastatic-prostate-cancer

  When a man is on ADT, recovery from a bone fracture takes longer than for other men. It is especially important for patients taking hormone therapy to speak with their doctor about how to plan for and manage the bone loss before a problem arises. Bone strength can also be decreased as a result of radiation and chemotherapy used to treat prostate cancer. […] When facing a metastatic prostate cancer diagnosis, many patients want to get a better understanding of their prognosis and survival rates in hope that this will help them make informed decisions about their treatment and care. While metastatic prostate cancer is not curable, many factors influence a patient’s prognosis and life expectancy. […] Factors that impact metastatic prostate cancer prognosis include: Extent of metastasis: The number and location of metastatic sites can affect prognosis. Patients with fewer metastases or metastases confined to the bones may have a better prognosis than those with widespread metastases or visceral involvement (such as liver or lung metastases). Overall health: A patient’s age, performance status, and the presence of other health conditions can influence their ability to tolerate treatments and impact their overall prognosis. Response to treatment: How well a patient responds to hormone therapy, chemotherapy, and other treatments can significantly affect their prognosis and survival. Patients who have a good initial response to treatment and maintain that response over time may have a better prognosis.

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