Targeting anoikis resistance in prostate cancer metastasis

Abstract

Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade anoikis and embark on a metastatic spread. Resistance to die via anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical anoikis signaling events will enable the therapeutic optimization of anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.

Figure 1

Acquisition of migratory and invasive potential enable cancer cell to detach from the primary site and enter circulatory and lymphatic system. Upon detachment, most of the cells lose the ECM mediated cell survival signals and subsequently lead to anoikis. However, some cancer cells acquire the ability to survive after loss of cell adhesion due to activation of anoikis resistance mechanisms and embark on the metastatic journey. These cancer cells adhere to the distant sites, proliferate and recruit a vascularity network at the secondary organ as distant metastasis tumors.

Figure 2

Programming anoikis induction. Upon cell detachment, anoikis signaling can be activated via three major pathways. (1), death receptor mediated pathway, (2), ECM-integrin cell survival pathway and (3), mitochondrial mediated pathway. (1), Activation of FAS/FADD in death receptor induces cleavage of caspase-8 and subsequently activate downstream caspase-3 to induce apoptosis. (2) ECM-epithelial cell interaction mediates integrin dependent activation of Talin1, FAK/SRC and ILK-1. Activation of ILK-1 mediates phosphorylation of GSK3β and recruitment of Snail. This signaling cascade activates PI3K/AKT cell survival signals. Loss of survival signals upon cell detachment, enhances cell susceptibility to apoptotic stimuli. (3). Cell detachment induces upregulation of pro-apoptotic protein, like Bim and down regulation of anti-apoptotic regulatory proteins such as BCL-2, which activate the cytochrome-C release from the mitochondria and subsequently trigger activation of Caspase-9 and 3 to induce apoptosis.