Trends in Pharmacological Sciences
OpinionTargeting integrin β4 for 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.
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