Anoikis Regulation: Complexities, Distinctions, and Cell Differentiation

Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

“…In summary, while there is a clear segregation of α6β4 forms in the normal intestinal mucosa where α6Aβ4cdtis expressed by the proliferative cells of the lower crypt and α6Bβ4ctd+ is mainly expressed by the quiescent and differentiated cells of the upper crypt and surface epithelium, cancer cells predominantly overexpress α6β4 under the α6Aβ4ctd+ hybrid form (Figure 3), which appears to mediate both cell proliferation and suppression of anoikis [39,52]. In summary, while there is a clear segregation of α6β4 forms in the normal intestinal mucosa where α6Aβ4cdt-is expressed by the proliferative cells of the lower crypt and α6Bβ4ctd+ is mainly expressed by the quiescent and differentiated cells of the upper crypt and surface epithelium, cancer cells predominantly overexpress α6β4 under the α6Aβ4ctd+ hybrid form (Figure 3), which appears to mediate both cell proliferation and suppression of anoikis [39,52]. Integrin α6β4 expressed in the human colonic mucosa.…”

“…In carcinoma cells, numerous studies have demonstrated that α6β4 promotes cell motility and invasive behaviour rather than stable anchoring to the extracellular matrix via a mechanism related to the one used for cell migration in wound healing in normal cells [36]. Since the discovery that α6β4 promotes colonic carcinoma cell invasiveness by activating the PI3K pathway [38], there have been a number of studies that have contributed to better documenting the potential of integrin α6β4 to regulate multiple signal transduction cascades involved in the promotion of cell proliferation, migration, invasion and suppression of anoikis [18,36,39]. While I invite the reader to refer to these seminal reviews [18,36,39] for further details about the multiple signalling transduction cascades that can be activated by α6β4 upon binding to its ligand, a few crucial elements are worth mentioning herein in the context of colorectal cancer ( Figure 2).…”

“…Since the discovery that α6β4 promotes colonic carcinoma cell invasiveness by activating the PI3K pathway [38], there have been a number of studies that have contributed to better documenting the potential of integrin α6β4 to regulate multiple signal transduction cascades involved in the promotion of cell proliferation, migration, invasion and suppression of anoikis [18,36,39]. While I invite the reader to refer to these seminal reviews [18,36,39] for further details about the multiple signalling transduction cascades that can be activated by α6β4 upon binding to its ligand, a few crucial elements are worth mentioning herein in the context of colorectal cancer ( Figure 2). First, is the ability of α6β4 to synergistically cooperate with oncogenic receptor tyrosine kinases such as those of the epidermal growth factor receptor family and c-Met, which via their downstream effectors, the Src family of kinases, trigger the phosphorylation of tyrosine residues in the cytoplasmic domain of the β4 subunit to enhance the signal [34].…”

“…Third is the apparent dual influence of α6β4 on cell survival. In most cell types, cell survival requires an α6β4-dependent PI3K activation and blocking α6β4-mediated adhesion trigger apoptosis [39]. However, using the RKO colon carcinoma cell line, Mercurio's team showed that the ability of α6β4 to promote or inhibit apoptosis depends on the p53 cell status.…”

“…MYC appears also as one key regulator of integrin expression since both ITGB4 and ITGA6 have MYC-responsive elements in their promoters as for ESPR1 that encodes a splicing factor that regulate ITGA6A expression. Adapted from [18,36,39,40].…”