An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK–AKT pathway

Leng, Chao; Zhang, Zhanguo; Chen, Weixun; Luo, Hongping; Song, Jia; Wang, Dong; Zhu, X.H; Chen, Xiaoping; Liang, Huifang; Zhang, Bixiang

doi:10.1016/j.canlet.2016.03.023

Cited by 83 publications

(67 citation statements)

References 38 publications

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“…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).…”

supporting

confidence: 91%

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

Bierie

Pierce

Kroeger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

302

233

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Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymallike triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+ cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC.cancer | heterogeneity | EMT | mesenchymal | ITGB4

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supporting

confidence: 91%

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

Bierie

Pierce

Kroeger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

302

233

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“…Pluripotency is the ability of a cell to differentiate into any cell type and is a unique characteristic of embryonic stem cells (ESCs)19. Pluripotency transcription factors such as Sox2, Nanog, KLF4 and c-MYC, etc have been also suggested to be oncogenes and may be implicated in the development of several cancers involving multiple signaling pathways including PI3K, AKT, etc2021222324. Previous reports have shown that the aforementioned transcription factors are regulated, at least in part, by pluripotency factors1925.…”

mentioning

confidence: 99%

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Liu

et al. 2017

Sci Rep

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Integrin β4 (ITGB4) is a transmembrane receptor involved in tumorigenesis and the invasiveness of many cancers. However, its role in hepatocellular carcinoma (HCC), one of the most prevalent human cancers worldwide, remains unclear. Here, we examined the involvement of ITGB4 in HCC and explored the underlying mechanisms. Real-time PCR and immunohistochemical analyses of tissues from 82 patients with HCC and four HCC cell lines showed higher ITGB4 levels in tumor than in adjacent non-tumor tissues and in HCC than in normal hepatic cells. Silencing of ITGB4 repressed cell proliferation, colony forming ability and cell invasiveness, whereas ectopic expression of ITGB4 promoted the proliferation and invasion of HCC cells and induced epithelial to mesenchymal transition (EMT) in parallel with the upregulation of Slug, as shown by transwell assays, WB and immunocytochemistry. Knockdown of Slug reduced cell viability inhibited invasion and reversed the effects of ITBG4 overexpression on promoting EMT, and AKT/Sox2-Nanog may also be involved. In a xenograft tumor model induced by injection of ITGB4-overexpressing cells into nude mice, ITGB4 promoted tumor growth and metastasis to the lungs. Taken together, our results indicate that ITGB4 plays a tumorigenic and pro-metastatic role mediated by Slug and suggest IGTB4 could be a prognostic indicator or a therapeutic target in patients with HCC.

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“…ITGB4 expression is increased in a variety of malignancies including breast cancer cells (6,7). ITGB4 is involved in and can enhance multiple signaling pathways, including ErbB2 (8,9), PI3K (10,11), FAK/AKT (12,13), and c-Met (14,15), to promote tumor progression (16). Exosome proteomics revealed the exosomal ITGB4 was associated with lung metastasis (17,18).…”

Section: Introductionmentioning

confidence: 99%

Integrin β4–Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis

Ruan

Lin

Zhu³

et al. 2020

Cancer Research

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Integrin b4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/ anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumordraining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4targeted immunotherapy reduced not only the number of ITGB4 high CSCs in residual 4T1 and SCC7 tumors but also their tumorinitiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy. Significance: Immune targeting of ITGB4 may represent a novel approach to improve the efficacy of current cancer immunotherapies.

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An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK–AKT pathway

Cited by 83 publications

References 38 publications

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

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

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Integrin β4–Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis

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