Stromal cells in prostate carcinogenesis

The role of stromal cells on the initiation and promotion of carcinogenesis has been studied over many years. This concept was pioneered from previous studies showing [1-3] that tumor stroma, termed as CAF (cancer associated fibroblast), TAS (tumor associated stroma), or RS (reactive stroma), is often different from the normal stroma [1]. Normal prostate stromal cells play a protective role and maintain growth quiescence within the prostatic tissue. Some investigators have demonstrated in animal studies that when normal prostate stromal cells are associated with malignant epithelial cells, there is a decrease in the proliferation rate [4,5] and an apparent loss of former malignant properties of epithelial cells[6]. Some studies have also shown restriction of growth of epithelial cells and induction into a more differentiated phenotype [7]. Recombination studies using Dunning rat adenocarcinoma revealed that normal stromal environment may override the effects of oncogenic mutations in tumor cells [8]. Normal stromal cells therefore, retain properties of growth control and can prevent the proliferation of cells undergoing neoplastic transformation.

Modification of stromal environment is necessary for carcinogenesis and it is adequately evident on observation of stroma immediately adjacent to carcinoma cells in several tumors [1]. Recombination experiments by viral transfection of oncogenes myc and ras into urogenital sinus mesenchyme and epithelium have illustrated that changes are required in both epithelium and stroma for prostatic carcinogenesis to occur [9]. The principal stromal cells - smooth muscle cells and fibroblasts undergo a phenotype switching to emerge as myofibroblasts during tu-morigenesis. Morphologically and on the basis of cytoskeletal protein expression, myofibro-blasts are an intermediate between fibroblasts and smooth muscle cells [10,11]. They are identified by increased expression of vimentin, alpha actin and decreased expression of calpo-nin and smooth muscle myosin. Other phenotypic changes seen in the cancer associated stro-ma include abnormal migratory behavior in vitro, alterations in the cell surface molecules, expression of prostaglandin synthesizing enzymes, alterations in extra cellular matrix (ECM) and altered expression of growth factors - platelet derived growth factor (PDGF), insulin-like growth factor (IGF) 1 & 2, transforming growth factor beta 1(TGF-b1), hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) [1]. There are several possible factors which promote the modification of normal stromal cells into cancer associated stroma. Some signals from epithelial cancer cells to surrounding stromal cells have been shown to alter the function of stromal cells and ECM production, such as TGF-b1, which induces stromal secretion of 'ver-sican' an extracellular chondroitin sulfate proteoglycan [12]. In a hormone sensitive cell model, variations in ECM have been shown to regulate stromal cell phenotype [13]. There is also evidence that the genetic modifications seen in the cancer associated stroma [14] are a result of epithelial to mesenchymal transitions of previously genetically abnormal epithelial cells. There is a genome-wide change in stromal genes associated with prostate cancer. In an analysis by Rowley et al. [15], when compared with normal stroma, a total of 544 unique genes were significantly higher in the reactive stroma and 606 unique genes were lower. Gene ontology analysis revealed significant alterations in a number of novel processes in prostate cancer reactive stro-ma, including neurogenesis, axonogenesis, and the DNA damage/repair pathways, as well as an evidence of increased number of stem cells in prostate cancer reactive stroma.

Alternatively, in the 'reactive stroma' hypothesis [11] the stroma of prostate cancer has been correlated with the granulation tissue in wound repair mechanism with reference to similar biological responses. As in any wound repair situation the microenvironment would be expected to be growth promoting which correlates with the promotion of survival and proliferation of carcinoma cells by stroma in prostatic carcinogenesis. Tissue recombination studies have demonstrated that human prostatic tumor associated stroma can promote carcinogenesis in genetically initiated human prostatic epithelial cells [1,16]. The results of this experiment revealed an important inference that the cancer associated stroma, when formed, exhibit a significant role in the epithelial cells promoting prostate carcinogenesis.

In contrast, some investigators [17] have shown that tumor associated stromal cells inhibit epithelial cell growth by production of a specific inhibitory factor termed as prostatic epithelium inhibiting factor (PEIF). The expression of this factor by stromal cells was only in the conditioned media collected from isolated stromal cell subcultures. Later in another experiment [18], stromal cells derived from surgically obtained prostatic carcinoma specimens were co-cultured with PC-3 cells using double layer soft agar system. It was noticed that growth of PC-3 cells was inhibited by the stromal cells.

The diversity in stromal cell function in inhibiting or promoting epithelial cell growth may be explained by the heterogeneity of stromal cells in the stromal compartment. During carcino-genesis, the stromal cells display heterogeneity in their morphology as smooth muscle cells, fibroblasts and myofibroblasts. Also, they are heterogenous in AR expression as AR positive and AR negative cells. It may be possible that the presence and absence of AR in stromal cells can dictate cancer epithelial cell proliferation or growth suppression.

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