The progression of prostate cancer is believed to occur in sequential steps. A primary tumor forms, becomes aggressive, disseminates aggressive cells that invade a secondary site, forms a metastasis, the metastases metastasize, and a lethal phenotype emerges. Empirical findings challenge this linear view of disease progression. It has been demonstrated that prostate cancer disseminates to and invades the bone marrow of patients who present with organ-confined early stage primary disease. Although these cells (DTCs) are present at prostatectomy - biochemical evidence of disseminated disease does not present for several years and the cells themselves lack proliferation markers. These findings suggest a latent-phase in which the majority of Homo sapien bone disseminated prostate cancer cells lack metastatic potential. This raises the following questions:
1) Metastogenesis by DTCs:
- Are bone metastases in Homo sapiens the slow expansion of rare non-dormant clones or is there a time delayed recurrent secondary-site specific "metastogenic-transformation" that activates skeletal tumor formation by DTCs?
2) Heterogeneity of DTCs:
- how many molecular-phenotypes of dormancy are there amongst Homo sapien prostate cancer DTCs?
- how many dormancy escape mechanisms are there?
- are dormancy escape mechanisms redundant, convergent, or divergent?
- is the escape route from dormancy ultimately taken by DTCs predestined by clonal origins or selected for by recurrent secondary transformations at the metastatic site?
3) Seed-Soil relationship of DTC dormancy and the bone microenvironment:
- is dormancy a byproduct of selection for dormant clones by the metastatic process?
- is dormancy induced by the bone marrow microenvironment/metastatic niche?
- what microenvironmental cues (molecular, structural, or mechanical) would confer/ablate tumor cell dormancy?
- can dormant DTCs “prime-the-soil” through microenvironmental manipulation for future tumor formation?
- Holcomb IN, Grove DI, Kinnunen M, Friedman CL, Gallaher IS, Morgan TM, Sather CL, Delrow JJ, Nelson PS, Lange PH, Ellis WJ, True LD, Young JM, Hsu L, Trask BJ, Vessella RL. Genomic alterations indicate tumor origin and varied metastatic potential of disseminated cells from prostate cancer patients. Cancer Res. 2008 Jul 15;68(14):5599-608.