Clinical significance of the integrin α6β4 in human malignancies

Abstract

Integrin α6β4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6β4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor promoting transcription factors such as the NFATs and NFkB. Expression of integrin α6β4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6β4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6β4 that contribute to tumor progression.

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

“…This result was consistent with previous mechanistic work, which demonstrated that ITGB4 can promote activation of the MET protooncogene receptor tyrosine kinase, epidermal growth factor receptor, focal adhesion kinase, SRC protooncogene nonreceptor tyrosine kinase, phosphoinositide 3-kinase, AKT serine/threonine kinase (AKT), mitogen-activated protein kinase kinase 1/2, mitogen-activated protein kinase (ERK) 1/2, and ras homolog family member A signaling pathways that are known to enhance tumor progression (13)(14)(15). Importantly, ITGB4 has been previously shown to be enriched in TNBC breast cancer patient tissues (16).…”

“…Indeed, ITGB4 itself has been shown to be transcriptionally repressed by ZEB1 (32), and ITGB4 has been shown to promote tumor progression in a number of previously published studies (13). Accordingly, we speculated that ectopic expression of ITGB4 in the SUM159 ITGB4 lo cells might, on its own, alter the histopathological phenotype of tumors arising from these carcinoma cells.…”

MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling

“…21,22,28,29 Both integrins and MUC5AC share the von Willebrand factor domain, 30,31 which is required for dimerization or oligomerization. We hypothesized that the presence of von Willebrand factor domains in both integrins and MUC5AC may lead to their interaction with each other.…”

“…20 In addition, integrins appear to be specifically associated with growth factors and oncogenes for tumor progression. 19,21,22 MUC5AC induces migration of pancreatic cancer cells by enhancing the integrins expression. 23 However, functional significance and co-existence of MUC5AC and integrins in lung cancer is not well elucidated.…”

α6β4 Integrin Directs Alveolar Epithelial Migration

“…Indeed, malignant invasive and metastatic machinery often co-opt migratory signaling pathways (13). Furthermore, a 6 b 4 integrin is up-regulated in lung cancer cells, and a high level of expression is a negative prognostic factor for patients with lung cancer (14). The majority of the data presented here is generated using A549 cells, an adenocarcinoma cell line, which could restrict the applicability of the results to malignancies.…”