Src: Marker or Actor in Prostate Cancer Aggressiveness

Abstract

A key question for urologic practitioners is whether an apparently organ-confined prostate cancer (PCa) is actually aggressive or not. The dilemma is to specifically identify among all prostate tumors the very aggressive high-grade cancers that will become life-threatening by developing extra-prostatic invasion and metastatic potential and the indolent cancers that will never modify a patient’s life expectancy. A choice must be made between several therapeutic options to achieve the optimal personalized management of the disease that causes as little harm as possible to patients. Reliable clinical, biological, or pathological markers that would enable distinctions to be made between aggressive and indolent PCas in routine practice at the time of initial diagnosis are still lacking. The molecular mechanisms that explain why a PCa is aggressive or not are also poorly understood. Among the potential markers and/or actors in PCa aggressiveness, Src and other members of the Src kinase family, are valuable candidates. Activation of Src-dependent intracellular pathways is frequently observed in PCa. Indeed, Src is at the cross-roads of several pathways [including androgen receptor (AR), TGFbeta, Bcl-2, Akt/PTEN or MAPK, and ERK …], and is now known to influence some of the cellular and tissular events that accompany tumor progression: cell proliferation, cell motility, invasion, epithelial-to-mesenchymal transition, resistance to apoptosis, angiogenesis, neuroendocrine differentiation, and metastatic spread. Recent work even suggests that Src could also play a part in PCa initiation in coordination with the AR. The aim of this review is to gather data that explore the links between the Src kinase family and PCa progression and aggressiveness.

Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2

“…Numerous previous studies addressing SFKs in the prostate focussed on oncologic context (Cai et al, ; Montero et al, ; Varkaris et al, ; Vlaeminck‐Guillem et al, ). In prostate cancer cells, SFKs may promote migration, which depends on actin dynamics and cytoskelet organization (Slack et al, ; Sabbota et al, ).…”

Targeting Neuroendocrine Prostate Cancer: Molecular and Clinical Perspectives

“…Src kinase is another important player in the EMT process as it is activated by several neuropeptides, including CgA, NSE, serotonin, neurophysin, bombesin, and synaptophysin. Through direct physical interaction with the AR, Src is able to phosphorylate the AR and thereby induce ligand-independent AR activation (one of the key mechanisms of castration-resistant PC) ( 38 ). Neuropeptides, notably bombesin were also found to enhance early growth response 1 (Egr-1) expression leading to increased human protease-activated receptor 1 (PAR1) expression and function directly correlating with invasiveness and the degree of PC malignancy ( 39 ).…”

Editorial: Prostate Cancer: What We Know and What We Would Like to Know

“…Although the identification and development of more specific diagnostic biomarkers are considered important, the major focus in translational prostate cancer research is the identification of potential “quantitative variables” to detect clinically significant prostate cancers. As reported by Vlaeminck-Giullem et al ( 10 ), the current dilemma is to specifically distinguish among all prostate tumors the very aggressive high-grade cancers that will become life threatening by developing extra-prostatic invasion and metastatic potential from the indolent cancers that will never modify a patient’s life expectancy. At molecular level, Src and other members of the Src kinase family have been proposed as potential candidates ( 10 ).…”

“…As reported by Vlaeminck-Giullem et al ( 10 ), the current dilemma is to specifically distinguish among all prostate tumors the very aggressive high-grade cancers that will become life threatening by developing extra-prostatic invasion and metastatic potential from the indolent cancers that will never modify a patient’s life expectancy. At molecular level, Src and other members of the Src kinase family have been proposed as potential candidates ( 10 ). Recently, it has been shown that the activation of Src-dependent intracellular pathways is frequently observed in clinically significant prostate cancer ( 11 ).…”

“…Through both direct and indirect interaction with the androgen receptor (AR), Src reinforce the proliferative and anti-apoptotic actions of the AR, even in the absence of specific ligands. These molecular mechanisms constitute a solid rationale in favor of the use of Src inhibitors in managing patients with prostate cancer ( 10 , 12 ). On the other hands, decades of research are now leading to therapeutics that target the molecular mechanisms of the cancer-specific immune response ( 13 ).…”