Molecular Mechanisms and Immune Regulation in Prostate Cancer: A Review.

Prostate cancer is formed of a heterogeneous population of cancer cells with different biological properties. They initially form a small part of the normal stromal microenvironment but are able, through cell-to-cell contact and via exosomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, and chemokines and cytokines, to transform the normal stromal cells into tumour-associated cells to create an immunosuppressive environment as well as inhibit the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement membrane but also the extracellular matrix, allowing the exosomes to disseminate via the circulation. Exosomes are organotrophic, homing in to specific tissues such as bone. Here, they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environment, as well as induce changes in the host cells and produce myeloid-derived suppressor cells, of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response, they are able to implant in the premetastatic niche, transforming it into the metastatic niche. Here, they enter a latent state or dormancy period, which may last for months or years but later can "awake" to form metastasis. This review critically analyses the cellular and molecular mechanisms, which produce this process from cellular aspects to the signalling pathways responsible for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells, from cellular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNAs and long non-coding RNAs in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survival at 10 years. Therefore, a precision medical approach may improve the biochemical free survival rate without affecting the role of the signalling pathways in normal cells. This includes the modulation of interleukin expression, elimination of exosomes, or the inhibition of important enzymes, such as MMP-2, thus mitigating the residual recurrence risk that persists with conventional therapy.