The Cohesive Metastasis Phenotype in Human Prostate Cancer

Abstract

A critical barrier for the successful prevention and treatment of recurrent prostate cancer is detection and eradication of metastatic and therapy-resistant disease. Despite the fall in diagnoses and mortality, the reported incidence of metastatic disease has increased 72% since 2004. Prostate cancer arises in cohesive groups as intraepithelial neoplasia, migrates through muscle and leaves the gland via perineural invasion for hematogenous dissemination. Current technological advances have shown cohesive-clusters of tumor (also known as microemboli) within the circulation. Circulating tumor cell (CTC) profiles are indicative of disseminated prostate cancer, and disseminated tumor cells (DTC) are found in cohesive-clusters, a phenotypic characteristic of both radiation- and drug-resistant tumors. Recent reports in cell biology and informatics, coupled with mass spectrometry, indicate that the integrin adhesome network provides an explanation for the biophysical ability of cohesive-clusters of tumor cells to invade thorough muscle and nerve microenvironments while maintaining adhesion-dependent therapeutic resistance. Targeting cohesive-clusters takes advantage of the known ability of extracellular matrix (ECM) adhesion to promote tumor cell survival and represents an approach that has the potential to avoid the progression to drug- and radiotherapy-resistance. In the following review we will examine the evidence for development and dissemination of cohesive-clusters in metastatic prostate cancer.

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…TGFβ signaling activated in bone metastases regulates the prometastatic and pro-survival properties of PCa cells including expression of CXCR4 and increase in ALDH activity [190,[203][204][205]. PCa cells have deregulated expression of integrins [206] that play critical roles in prostate tumor cell invasion and metastatic development [207]. The PCa cell population positive for α2β1 integrin expression is enriched for tumor-initiating cells [30,208].…”

Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3

“…There is a marked selection for increased integrin α6β1 expression and decreased integrin β4 expression in primary prostate cancers (5,7,43). Elevated integrin α6β1 is associated with increased invasiveness, lymph node metastasis, and bone metastasis (43,44).…”

“…Our studies further emphasize the importance of the tumor microenvironment when attempting to understand mechanisms of castration-resistance. Laminin is a major ECM component in lymph nodes and bone, the major sites for prostate cancer metastasis (8,9), and integrin α6β1 is the major integrin expressed on prostate tumors in these tissues (43,44). In cell culture models of prostate cancer, where cells adhere to RGD-containing ECM like fibronection or vitronectin found in serum that coats the plastic petri dish, the effects of laminin-specific integrin signaling are missed.…”

Hypoxia-Induced PIM Kinase and Laminin-Activated Integrin α6 Mediate Resistance to PI3K Inhibitors in Bone-Metastatic CRPC

“…1C). CAM-DR has been shown to cause therapeutic resistance in prostate cancer [7], and the laminin-specific integrin, α6β1 (ITGα6), is the primary integrin expressed in prostate cancer [39]. Thus, we sought to determine whether integrin signaling was enhanced following ADT.…”

“…Two bone-enriched environmental factors, the extracellular matrix (ECM) and hypoxia, are independently established mechanisms for drug resistance, but their mechanistic role in CRPC or drug resistance in bone metastasis in general has received limited attention. Cell adhesion to the ECM by integrins is a major mediator of chemotherapy and radiation resistance in many cancers, including prostate cancer [6][7][8]. Blocking adhesion to the ECM sensitizes prostate cell lines to both radiation and chemo therapies [9][10][11].…”