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. 2013 Nov 19;74(3):314–320. doi: 10.1002/pros.22753

Fig I.

Fig I

The systems pathobiology of prostate cancer. Prostate cancer develops and evolves as a complex adaptive system in a dynamic manner over time. Different cancer clones (tumor cell heterogeneity) evolve through inherent genomic and epigenomic instability as well as in response to therapeutic pressure. It appears that multiple host cells, including hematopoietic stem cells, mesenchymal stem cells, endothelial progenitors, cancer-associated fibroblasts, and inflammatory mononuclear cells (T-, B-, and monocytes) not only contribute to the pathogenesis of CRPC within the primary and metastatic microenvironments, but also traffic freely between tumor sites 16,17. Three phenotypes/genotypes of CRPC after treatment with second-generation agents appear to be increasing in prevalence and remain resistant to treatment: NeuroEndocrine Prostate Cancer (NEPC), Persistent AR—Dependent Prostate Cancer (PADPC), and Androgen Receptor Pathway Independent Prostate Cancer (APIPC) (9,9a). It is clear that new treatment paradigms, taking into account cancer cell genetic and epigenetic pathways, contributing factors within the microenvironment, and the macroenvironment of the host/patient need to be developed for this diverse group of diseases.