The prostate cancer microenvironment

The morphology of a tumor may also influence in the biological responses of cancer cells to a specific therapy. Although most of the reports in cancer therapy utilize monolayer cultures, multicellular aggregates (spheres) are probably more important because reflects the three-dimensional structure for a real-time model representing a tumor, allowing to study the interaction of tumor cells with the microenvironment [105]. The fact that spheroids mimic the tumor microenvironment is also an important tool that may provide more accurate information about the biological and biochemical events occurring in solid tumors [106]. Therefore, the utilization of the spheres assay is an important approach for the in serial in vivo transplantation to verify self-renewal potential.

Although, sphere cells are generated, serially passaged, and maintained in undifferentiated phenotype under appropriate cell culture conditions, they need to be inoculated into animal models to confirm their ability to generate tumor growth [107, 108]. Indeed, substantial differences has been reported in the gene expression signatures on PC3 holoclones compared to parental PC3 cells, which appeared to be consequence of the distinct culture conditions used to growth each cell population [109]. Consistent with these observations, growing conditions also affected the expression of several genes in LNCaP cells [106]. A number of other variables such as the manner in which cells are isolated and the in vitro propagation of these cells before transplantation can cause tumor cells to become more aggressive as a result of new acquired mutations, which may affect the outcome of in vivo assays. Another critical parameters are to determine the variation on experimental conditions that may influence frequency estimates and to ensure the best animal model available in order to reproduce the tumor biology as it occurs in humans. For example, the limiting dilution data might be dramatically affected by the duration of data analysis [110] or by modification of xenotrans-plantation assay in non-obese diabetic severe combined immunodeficient (NOD/SCID) mice [111]. Therefore, a main concern for the application of this methodology is that sometimes, the animal models overstate the biology of cancer formation in humans.

Most of human prostate tumor cells have the ability to form spheres; however, the frequency of cells forming spheres is very heterogeneous across all cell lines. In this regard, the adaptation of tumor cells to non-adherent culture conditions may be a determinant in forming spheres [112]. Also, the holoclone-forming cells, which are smaller than paraclone cells, more adherent, highly clonogenic, and whose progeny forms almost exclusively growing colonies, in prostate cancer specimens with the highest clonogenic potential has been associated with stem cell phenotypes [113]. Of great importance is the fact that large holoclones were also consistently present in prostate cancer cell spheres [109, 114], suggesting that these spheres, which are sustained by tumor initiating cells with stem cell-like features, may have a strong self-renewal and pro-angiogenic capability [115]. These spheres were capable of forming new generations of spheres and retained proliferative capacity as well as clono-genic potential after serial passages [116]. These reports were supported by studies in which a minor subpopulation of spheres propagating cells with stem cell-like properties isolated from a series of prostate cancer models were capable of forming spheres, display significant increase in proliferation potential, initiate xenograft tumors with enhanced capacity, and were more drug resistant compared to monolayer cells [109, 117]. Accordingly, the expression of putative cancer stem cell markers such as ALDH1A1, CD44, CD133, showed strong correlation with prostate tumor progression and metastasis [92, 118, 119], while Nanog induction promoted castration-resistant tumor phenotype and tumor regeneration in the LNCaP cells [120].

There is no doubt that the microenvironment definitely affects the expression of multiples genes that may be more evident in spheroids in which the tumor cell interaction with the extracellular matrix may influence responses to prostate cancer treatment. Thus, the three-dimensional system should be included in pre-clinical experimental models to identify in prostate tumors the mechanisms that are related with tumor progression, and those that confer resistant to cancer therapies.

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