Opinion
Targeting integrin β4 for cancer and anti-angiogenic therapy

https://doi.org/10.1016/j.tips.2007.08.004Get rights and content

The integrins play key roles in the signaling networks that drive pathological angiogenesis and tumor progression. Integrin β4 is a laminin receptor upregulated in tumor cells and angiogenic endothelial cells. Biochemical studies have indicated that β4 combines with and enhances the signaling function of multiple receptor tyrosine kinases, including ErbB2, EGF-R and Met. Genetic studies have revealed that β4 signaling promotes both angiogenesis and tumorigenesis. Here, I discuss the hypothesis that β4 promotes both processes by amplifying receptor-tyrosine-kinase signaling. Therefore, I propose that a simultaneous blockade of β4 and receptor-tyrosine-kinase signaling represents a rational approach to cancer and anti-angiogenic therapy.

Introduction

During the transition from carcinoma in situ to invasive carcinoma, tumor cells undergo distinctive changes in cell adhesion and signaling 1, 2. They lose intercellular junctions, dissolve the underlying basement membrane and penetrate into the interstitial matrix. No longer restrained by the organized architecture of the tissue of origin, invading tumor cells attract stromal cells, such as macrophages, activated fibroblasts and angiogenic endothelial cells, which help them to evolve toward increasing malignancy [3]. Although most targeted therapies for cancer seek to exploit the dependency of tumor cells on the oncogenic mutations that foster their ability to proliferate and resist apoptosis, increasing evidence points to the potential benefit of also identifying and targeting the molecular elements that drive tumor progression [4].

The integrins play key roles in the signaling networks that drive tumor progression 1, 2. Upon ligand binding, integrins modify the organization of the cell's cytoskeleton and activate signals that regulate cells’ ability to survive, proliferate, and migrate in response to growth factors and cytokines 5, 6, 7. Because cancer cells can often survive and proliferate even if deprived of adhesion to the matrix, they are considered ‘anchorage-independent’. However, genetic experiments are revealing that neoplastic cells might be more dependent on specific integrins than normal cells and might benefit from integrin signals at various stages of tumor progression [2].

Unique among the 24 known mammalian integrins, the α6β4 integrin (henceforth integrin β4) is characterized by the fact that its β4 subunit has a 1017 amino-acid-long domain, which has distinctive cytoskeletal and signaling functions [7]. The β4 integrin is upregulated in various tumor types [8], and recent studies have indicated that it combines with and enhances the signaling function of multiple oncogenic receptor tyrosine kinases (RTKs), such as ErbB2, EGF-R and Met 9, 10, 11. In addition, β4 is expressed in tumor blood vessels and promotes the invasive phase of tumor angiogenesis [12]. Here, I will discuss the genetic and biochemical evidence that has identified β4 as an attractive target for cancer and anti-angiogenic therapy.

Section snippets

The β4 integrin is upregulated in multiple prevalent tumor types

The β4 integrin was originally identified as a ‘tumor-specific’ protein (‘Tumor-Specific’ Protein 180, TSP180) upregulated in metastatic variants of mouse lung carcinoma and melanoma cell lines 13, 14. Subsequent studies provided evidence that the expression of β4 increases significantly during malignant progression in squamous carcinomas of multiple tissues, including head and neck, skin, cervix, and lung 15, 16, 17, 18, 19. In addition, although β4 is not expressed in normal thyroid cells, it

β4 signaling

The β4 integrin possesses two contrasting functions – stable adhesion and pro-invasive signaling – both encoded by its distinctive, long cytoplasmic tail. Unlike other integrins, which accumulate at focal contacts and interact with the actin cytoskeleton, β4 promotes the assembly of distinctive adhesive junctions, the hemidesmosomes, which mediate stable adhesion by connecting the intracellular keratin cytoskeleton to the basement membrane [29]. Thus, β4 undoubtedly performs a major adhesive

Cell biological studies

The effects of β4 signaling on tumor cell behavior have been examined predominantly through genetic manipulation and antibody treatment of established carcinoma cell lines. As mentioned above, β4 combines with the EGF-R, ErbB-2 and Met RTKs, which are often mutated or amplified during tumor progression. Several lines of evidence suggest that deregulated joint β4-RTK signaling contributes to carcinoma invasion and growth. First, introduction of wild-type but not signaling-defective β4 enhances

Genetic studies

Tumor initiation and progression to metastasis are complex biological processes driven by genetic and epigenetic changes that are selected for because they provide tumor cells with a growth advantage in the context of their microenvironment. In contrast to in vitro and in vivo assays with established cancer cell lines, genetically engineered mouse models of cancer provide an opportunity to examine tumor initiation and progression as well as the response to targeted therapies as they occur in

Targeting β4 for cancer and anti-angiogenesis

Several monoclonal antibodies and small molecules interfering with the adhesive function of several integrins have been developed to treat a variety of conditions, including thrombosis, neoangiogenesis, bone resorption, and inflammation, and some of these drugs are already in the clinic [52]. Although some of these inhibitors may function as partial agonists because they induce integrin activation and association with the cytoskeleton, they generally fail to activate integrin signaling because

Conclusion and perspective

The evidence reviewed here identifies the β4 integrin as an attractive target for anti-angiogenesis and cancer therapy. In particular, it indicates that agents able to disrupt β4 signaling will increase the therapeutic efficacy of existing targeted therapies for ErbB2-positive human breast cancers and VEGF-driven retinal neovascularization. Additional genetic studies will need to determine whether the effect of β4 signaling on tumorigenesis is limited to malignancies initiated by specific

Acknowledgements

Because of space constraints, I was unable to cite many excellent papers on integrin β4. I apologize to the authors of these papers. I wish to thank members of my laboratory for discussions. Research in my laboratory is supported by grants from the NIH.

References (56)

  • L.M. Shaw

    Activation of phosphoinositide 3-OH kinase by the α6β4 integrin promotes carcinoma invasion

    Cell

    (1997)
  • M.M. Santoro

    The MSP receptor regulates α6β4 and α3β1 integrins via 14-3-3 proteins in keratinocyte migration

    Dev. Cell

    (2003)
  • R. Falcioni

    α6β4 and α6β1 integrins associate with ErbB-2 in human carcinoma cell lines

    Exp. Cell Res.

    (1997)
  • A.S. Clarke

    Activation of the p21 pathway of growth arrest and apoptosis by the β4 integrin cytoplasmic domain

    J. Biol. Chem.

    (1995)
  • R.E. Bachelder

    Activation of p53 function in carcinoma cells by the α6β4 integrin

    J. Biol. Chem.

    (1999)
  • V.M. Weaver

    β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium

    Cancer Cell

    (2002)
  • T. Van Dyke et al.

    Cancer modeling in the modern era: progress and challenges

    Cell

    (2002)
  • W.J. Muller

    Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene

    Cell

    (1988)
  • A. Astolfi

    Gene expression analysis of immune-mediated arrest of tumorigenesis in a transgenic mouse model of HER-2/neu-positive basal-like mammary carcinoma

    Am. J. Pathol.

    (2005)
  • J.D. Hood et al.

    Role of integrins in cell invasion and migration

    Nat. Rev. Cancer

    (2002)
  • W. Guo et al.

    Integrin signalling during tumour progression

    Nat. Rev. Mol. Cell Biol.

    (2004)
  • M.J. Bissell et al.

    Putting tumours in context

    Nat. Rev. Cancer

    (2001)
  • C.K. Miranti et al.

    Sensing the environment: a historical perspective on integrin signal transduction

    Nat. Cell Biol.

    (2002)
  • F.G. Giancotti et al.

    Positional control of cell fate through joint integrin/receptor protein kinase signaling

    Annu. Rev. Cell Dev. Biol.

    (2003)
  • A. Mariotti

    EGF-R signaling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion

    J. Cell Biol.

    (2001)
  • S.J. Kennel

    Analysis of surface proteins of mouse lung carcinomas using monoclonal antibodies

    Cancer Res.

    (1981)
  • R. Falcioni

    Expression of tumor antigen correlated with metastatic potential of Lewis lung carcinoma and B16 melanoma clones in mice

    Cancer Res.

    (1986)
  • C. Van Waes

    The A9 antigen associated with aggressive human squamous carcinoma is structurally and functionally similar to the newly defined integrin α6β4

    Cancer Res.

    (1991)
  • Cited by (122)

    • A mutation found in esophageal cancer alters integrin β4 mRNA splicing

      2020, Biochemical and Biophysical Research Communications
    • Targeting integrin pathways: mechanisms and advances in therapy

      2023, Signal Transduction and Targeted Therapy
    View all citing articles on Scopus
    View full text