Since 1976, Surveillance Epidemiology End Results (SEER) began collecting ethnicity data for the National Cancer Institute. The incidence of prostate cancer (PCa) among African American men (AAM) has been 60–70% higher than any other ethnicity and mortality rate 2 to 3 times greater than European American men (EAM), and those data have not changed. We reported in 2010 that PCa grows faster among AAM compared to EAM. In 2013, we utilized bioinformatics and ingenuity gene network analysis and in silico analysis to identify driver genes responsible for “racial” disparity. Genes associated with lipid metabolism were more expressed among EAM and genes associated with inflammation were more expressed among AAM. In 2021, we unraveled the network of the Ingenuity gene analysis and reported that the inflammatory genes, specifically proinflammatory cytokines and chemokines initiated multiple pathways. A literature review of these pathways showed that they induce castrate-resistant PCa (CRPC), metastasis, oxidative stress, DNA damage, cancer stem cells, lineage plasticity, and tumor heterogeneity. These genes and processes will be discussed in detail as to how they are initiated by proinflammatory cytokines and chemokines and how they act in a domino effect. Most importantly, how lineage plasticity changes the chemistry of the cancer stem cells of the original PCa so that it is no longer recognized by current therapy, chemotherapy, and immunotherapy. This suggests a paradigm change of current therapy is necessary to significantly reduce mortality of advanced PCa.
