Regulation of prostate cancer progression by the tumor microenvironment

Abstract

Prostate cancer remains the most frequently diagnosed cancer in men in North America, and despite recent advances in treatment patients with metastatic disease continue to have poor five-year survival rates. Recent studies in prostate cancer have revealed the critical role of the tumor microenvironment in the initiation and progression to advanced disease. Experimental data have uncovered a reciprocal relationship between the cells in the microenvironment and malignant tumor cells in which early changes in normal tissue microenvironment can promote tumorigenesis and in turn tumor cells can promote further pro-tumor changes in the microenvironment. In the tumor microenvironment, the presence of persistent immune infiltrates contributes to the recruitment and reprogramming of other non-immune stromal cells including cancer-associated fibroblasts and a unique recently identified population of metastasis-initiating cells (MICs). These MICs, which can also be found as part of the circulating tumor cell (CTC) population in PC patients, promote cancer cell transformation, enhance metastatic potential and confer therapeutic resistance. MICs act can on other cells within the tumor microenvironment in part by secreting exosomes that reprogram adjacent stromal cells to create a more favorable tumor microenvironment to support continued cancer growth and progression. We review here the current data on the intricate relationship between inflammation, reactive stroma, tumor cells and disease progression in prostate cancer.

Keywords: Exosomes; Metastasis; Metastasis-initiating cells; Prostate cancer; Tumor immune microenvironment; microRNA.

Figure 1. Key cell types in the prostate cancer tumor microenvironment

Multiple different cell types shown in Figure 1 have been identified in the prostate cancer stroma and have been found to participate in the development and progression of the disease. Most of the cell types have the potential to either support or promote growth and a summary of their different functions is outlined in the table in Figure 1.

Figure 2. MICs and MIC-secreted exosomes and extracellular matrix alter the tumor microenvironment to promote reprogramming of bystander dormant cells leading to their transformation and de-differentiation

In response to secreted factors from MICs and stromal cells as well as molecules release from the extracellular matrix, bystander dormant cells in prostate cancer can undergo oncogenic reprogramming via epigenetic demethylation of MIC-associated gene promoters. This alteration of bystander cells is mediated by activation of RANKL, FOXM1, and c-Myc to promote prostate cancer cells to undergo EMT and develop enhanced stemness, neuroendocrine and invasive/metastatic phenotypes leading to prostate cancer progression and metastasis. Emerging evidence in the literature suggests that the immune microenvironment surrounding prostate cancer cells can also be modified by extracellular vesicles to either promote or block tumor growth depending upon the nature of the factors transferred. Future studies may reveal novel therapeutic opportunities.