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How Prostate Cancer Cells Use Strategy Instead of Brute Force to Achieve Metastasis


How Prostate Cancer Cells Use Strategy Instead of Brute Force to Achieve Metastasis

Darron Tharp et al. Cancers (Basel).


Akin to many other cancers, metastasis is the predominant cause of lethality in prostate cancer (PCa). Research in the past decade or so has revealed that although metastatic manifestation is a multi-step and complex process that is orchestrated by distinct cellular and molecular mechanisms, the process in itself is an extremely inefficient one. It is now becoming increasingly evident that PCa cells employ a plethora of strategies to make the most of this inefficient process. These strategies include priming the metastatic sites ahead of colonization, devising ways to metastasize to specific organs, outsmarting the host defense surveillance, lying in a dormant state at the metastatic site for prolonged periods, and widespread reprogramming of the gene expression to suit their needs. Based on established, recent, and evolving lines of research, this review is an attempt to understand PCa metastasis from the perspective of military combat, wherein strategic maneuvering instead of brute force often plays a decisive role in the outcome.

Keywords: immune evasion; metastasis; prostate cancer; strategies for metastasis; tropism.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Various strategies devised by prostate cancer cells to overcome the odds of establishing metastasis: Metastasis in prostate cancer (PCa) is driven by several strategies, which include pre-metastatic niche formation, organo-tropism, reprogramming including chromatin remodeling, and immune involvement/evasion, and dormancy at the secondary site. CAFs: cancer associated fibroblasts, miRNA: micro RNA, TGF-β: tumor growth factor β, CTCs: circulating tumor cells, DTCs: disseminated tumor cells, CXCR4: chemokine (C-X-C motif) receptor type 4, CXCL12: (C-X-C motif) chemokine ligand 12, MMP9: matrix metalloproteinase 9, FOXA1: forkhead box A1, PRC2: polycomb repressive complex 2. EZH2: enhancer of Zeste Homolog 2. DNMT: DNA MethylTransferase, SOX2: sex determining region Y- box 2.
Figure 2
Figure 2
The refined vicious cycle model of prostate cancer bone metastasis that takes into account dormancy and reactivation of prostate cancer cells: release of prostate cancer (PCa) cells from the dormant state is primarily mediated by increased bone resorption, and leads to their reactivation and proliferation, thereby driving metastatic outgrowth in the bone microenvironment. The induction of dormancy in PCa cells is orchestrated by the interaction of receptors expressed on PCa cells [AXL family receptor tyrosine kinases (AXL, TYRO3 and MER), and Annexin II receptor] with the cognate ligands expressed on osteoblasts that include Annexin II and GAS6. The vicious cycle of PCa bone metastasis is mediated by the production of factors by PCa cells that increase bone resorption through enhanced interaction between RANKL expressing osteoblasts and RANK expressing osteoclasts. Release of growth factors such as BMPs and TGF-β from the bone milieu—that is brought about by bone resorption—further fuels the vicious cycle of bone destruction and growth of the metastatic lesions. CXCR4: chemokine (C-X-C motif) receptor type 4, CXCL12: (C-X-C motif) chemokine ligand 12, AXL: AXL receptor tyrosine kinase, TYRO3: TYRO3 protein tyrosine kinase, MER: mer receptor tyrosine kinase, GAS6: growth arrest specific 6.

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