Tissue and cell—cell interactions in prostate cancer progression (1995)

Prostate cancer is unique among human cancers in the wide discrepancy between the high prevalence of histologic changes recognizable as cancer (latent cancer) and the much lower prevalence of clinically recognizable disease (clinical cancer). Latent or incidental prostate cancer is often found at autopsy, affecting nearly 33% of all men older than 50 years, yet the number of new cases of clinically manifest prostate cancer represents only a small fraction of this latent disease. This discrepancy indicates that life-threatening prostate cancer results from progression of only a subset of the latent and clinically insignificant lesions and not the progression of all small tumors. Therefore, we must understand the underlying molecular and cellular determinants of prostate cancer progression. The role of tissue and cell-cell interactions in prostate cancer progression is complex. During early stages of progression, relatively normally organized stroma can suppress discrete steps in carcinogenesis. This phenomenon is exemplified by studies using the mouse prostate reconstitution (MPR) model system, where investigators showed that intrinsic properties of the mesenchyme can modulate the conversion of oncogene-initiated benign hyperplastic prostatic epithelium to the malignant phenotype When the ras and myc oncogenes were introduced into both the mesenchymal and epithelial compartments of the microdissected urogenital sinus, poorly differentiated prostate cancer was produced at a high frequency (more than 90%) in inbred C57BL/6 mice. In contrast, benign prostatic hyperplasia converted to cancer at a low frequency (less than 10%) in BALB/c MPR mice under similar conditions. Heterologous MPR composed of BALB/c mesenchyme and C57BL/6 epithelium or vice versa showed that intrinsic properties of BALB/c mesenchyme can arrest the progression of ras + myc-initiated C57BL/6 epithelium from benign hyperplasia to cancer. Further progression of prostate cancer beyond its earliest forms of the malignant phenotype leads to increasingly disorganized stroma, where inappropriate stromal cell-cancer cell interactions can occur. Such interactions may include endothelial cell-cancer cell, lymphocyte-cancer cell, and neuron-cancer cell interactions. In addition to stromal cell-cancer cell interactions, the direct interaction of cancer cells with other cancer cells may lead to the establishment of important selection criteria whereby subsets of prostate cancer cells progress to metastatic disease. Understanding these various cell-cell interactions requires additional experimental studies that address the molecular and cellular basis of prostate cancer progression using appropriate model systems that contain the critical cell types. Recently we modified the MPR model system to involve the use of p53 “knock-out” urogenital sinus tissue as a target for oncogene-initiated prostate cancer. Using this protocol, we produced metastatic prostate cancer from normal cells in vivo. Importantly, the organ specificity of the metastatic disease closely resembles that in humans, and thus we can study genetic and phenotypic variability throughout the course of progression. In addition, because we use recombinant retroviruses to transduce the initiating oncogenes, we can track clonal progression and determine common progenitors of organ-specific metastatic disease. This model should prove useful in dissecting important tissue and cell-cell interactions in prostate cancer progression. Cancer 1995;75:1885–91.