Cancer cells use laminin/integrin signaling pathways that promote tumor cell growth, invasion and metastasis
During the past decades, many studies have provided evidence for a role of laminin-binding integrins in tumorigenesis, both tumor-promoting and suppressive activities. As a major component of the basement membrane that forms the stem cell niche (Rodin et al., 2014) and because of the central role in the regulation of cancer stem cells (Qin et al., 2016), laminin/integrin mediated interactions is of high therapeutic interest in cancer treatment (Rabinovitz & Mercurio, 1997; Berg et al., 2016). Cancer stem cells (CSCs) represent a subset of tumor cells that typically exhibit the ability to self-renewal and often has multi-potent capabilities. Expression of various laminin subunits in the tumor microenvironment surrounding the CSCs subpopulation has been demonstrated to serve as a niche for CSCs and contribute to tumor progression (Qin et al., 2016).
The laminin 2 chain (for example in laminin-332) has been shown to be a molecular marker for cells with invasive properties and correlated with poor prognosis (Kang et al. 2013; Rani et al., 2013). Laminin-332 is known to support the stable anchoring of basal keratinocytes to the epidermal basement membrane via hemidesmosomes components and the α6β4 integrin (Ghohestani et al., 2001; Litjens et al., 2006; Nishiuchi et al., 2006). However, laminin-332 is also an important motility factor for wound healing as well as for melanoma cancer invasion (Kariya et al., 2012). Prostate cancer cells also been shown to bind to laminin-332 via integrin α6β4 that activate signaling pathways promoting tumor cell growth, invasion and metastasis (Berg et al., 2016). Govaere and coworkers identified a prominent role for laminin-332 as part of the stem cell nice in human hepatic tumors where laminin-332 promotes stemness and protects the hepatic cancer cells against chemotherapy (Govaere at al., 2015).
Chang et al. show that breast cancer stem cells produce alpha-5 laminin matrix that promotes self-renewal and tumor initiation via α6β1 integrin interaction and activation of the Hippo transducer TAZ. TAZ also regulates the transcription of alpha-5 laminin, establishing a positive feedback loop that contributes to stemness in breast cancer (Chang et al., 2014).
In a publication by Fennewald et al, they showed that head and neck squamous cell carcinoma cell lines bind to laminin-511 under lymphodynamic low shear stress (consistent with lymph flow), mediated by β1 integrins interactions (Fennewald et al., 2012).
A publication by Kaemmerer et al. show that ovarian cancer cells cultured GelMA/LN411 spheroids result in higher reproducibility, less complexity and better comparability between different groups than traditional cell monolayer. Culture of ovarian cancer celsl in GelMA/LN411 spheroids results in higher reproducibility, less complexity and better comparability between different groups than traditional cell monolayer approaches (Kaemmerer et al., 2014).
Laminin-521 provides a good support for culture of various tumor cells of the nervous system
Laminin-521 promotes pluripotent stem cells survival, migration and stimulates cell proliferation over differentiation (Miyazaki et al., 2008; Rodin et al., 2014). Naturally, laminin-521 has also been shown to provide a good support for culture of various cancer cells, such as neuroblastoma, glioblastoma and medulloblastoma cells.
Gene expression analysis of different neuroblastoma cell lines show high expression of alpha-5 and alpha-4, beta-1 and beta-2 laminin chains, indicating expression of laminin-521, -511, -411 and -421 (unpublished data). Indeed, laminin-521 work well for culture of neuroblastoma cell lines.
Laminin-521 even support culture of medulloblastoma cells which is otherwise difficult to maintain in vitro (unpublished data).
In a publication by Ma et al., the authors showed that alpha-4 and alpha-5 laminins have specific effects in promoting the stemness of glioma cells, both at gene and protein expression level. In collaboration with a 3D context, U251 glioblastoma cells showed substantially upregulation of integrin α6β4 and enhanced clonogenicity on laminin-521, -511, -421 and -411 (Ma et al., 2016).
- The integrin alpha6beta4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin-containing motility structures. Rabinovitz & Mercurio. J Cell Biol., 1997
- Selection and Characterization of an α6β4 Integrin blocking DNA Aptamer. Berg et al. Molecular Therapy—Nucleic Acids, 2016
- Effect of laminin-332 on motility and invasion in bladder cancer. Kang et al., Kaohsiung J. Med. Sci. 2013
- Assessment of laminin-5 in oral dysplasia and squamous cell carcinoma. Rani et al. J. Oral Maxillofac. 2013
- Laminins and cancer stem cells: Partners in crime? Qin et al.,Seminars in Cancer Biology, 2016
- Molecular organization of the cutaneous basement membrane zone. Ghohestani et al. Clin Dermatol., 2001
- Current insights into the formation and breakdown of hemidesmosomes. Litjens et al. Trends Cell Biol., 2006
- Ligand-binding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactionsusing recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins. Nishiuchi et al. Matrix Biol., 2006
- Polymerized Laminin-332 Matrix Supports Rapid and Tight Adhesion of Keratinocytes, Suppressing Cell Migration. Kariya et al. PLOS ONE, 2012
- Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche. Govaere et al. Journal of hepatology, 2015
- A laminin 511 matrix is regulated by TAZ and functions as the ligand for the a6Bb1 integrin to sustain breast cancer stem cells. Chang et al. Research communication, 2015
- Laminin Interactions with Head and Neck Cancer Cells under Low Fluid Shear Conditions Lead to Integrin Activation and Binding. Fennewald et al. Journal of biological chemistry, 2012
- Gelatine methacrylamide-based hydrogels – an alternative 3D cancer cell culture system. Kaemmerer et al. Acta Biomaterialia, 2014
- Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment. Rodin et al. Nat Commun., 2014
- Recombinant human laminin isoforms can support the undifferentiated growth of human embryonic stem cells. Miyazaki et al.,Biochem Biophys Res Commun., 2008
- Collaboration of 3D Context and Extracellular Matrix in the Development of Glioma Stemness in a 3D Model. Ma et al. Biomaterials, 2015