Mechanism of anchorage-independency and tumor formation of cancer cells: possible involvement of cell membrane–bound laminin-332
Cancer cells are characterized by anchorage-independency and tumor formation. Involvement of laminin-332 in the pathogenesis of cancer has also been reported. I present a theory that can explain these characteristics together. Proliferating keratinocytes in wound healing produce and deposit laminin-332, which is shown in the provisional basement membrane of a wound. In association with wound closure, expression of LG4/5 domain on the α3 chain of laminin-332 disappears, implicating cleavage of LG4/5 domain. LG4/5 domain expression indicates that laminin-332 prior to the cleavage is bound to the cell membrane, because LG4/5 domain is a cell binding site. In this binding, heparan sulfate proteoglycan on the cell surface seems to be the acceptor for LG4/5 domain. I named this laminin “cell membrane–bound laminin-332” (ML332). ML332 would then bind to integrin α3β1 via LG1-3 domain, the integrin binding site, and activate FAK and the following Ras/MAPK pathway. Therefore, ML332 eliminates the need for proliferating keratinocytes to bind to processed laminin-332 secreted and deposited into the basement membrane for their proliferation (anchorage-independency). This may hold true of every proliferating epithelial cell, either benign or malignant. Whereas wound closure deprives keratinocytes of anchorage-independency, such events do not occur in cancer cells, and cancer cells maintain anchorage-independency. In the basement membrane formation by epithelial cells, short arms of laminin-332 anchored to the cell membrane bind each other and generate a meshwork polymer. This is the three-arm interaction model. In a similar manner, short-arm interactions between adjacent cancer cells may occur and induce tumor formation.
KeywordsWound healing Unprocessed laminin-332 LG4/5 domain Focal adhesion kinase Epithelial cell proliferation
Compliance with ethical standards
This research does not involve human participants or animals.
Conflict of interest
The author declares that he has no conflict of interest.
- Katayama H, Yamane Y, Furukawa Y, Kitagawa S, Nakamura Y, Yoshino K (2008) Activation of focal adhesion kinase in detached human epidermal cancer cells and their long-term survival might be associated with cell surface expression of laminin-5. Acta Derm Venereol 88:100–107PubMedCrossRefPubMedCentralGoogle Scholar
- Lam AT, Li J, Chen AK, Reuveny S, Oh SK, Birch WR (2014) Cationic surface charge combined with either vitronectin or laminin dictates the evolution of human embryonic stem cells/microcarrier aggregates and cell growth in agitated cultures. Stem Cells Dev 23:1688–1703PubMedPubMedCentralCrossRefGoogle Scholar
- Nishiuch R, Takagi J, Hayashi M, Ido H, Yagi Y, Sanzen N, Tsuji T, Yamada M, Sekiguchi K (2006) Ligand-bin Tding specificities of laminin-binding integrins: a comprehensive survey of laminin-integrin interactions using recombinant alpha3beta1, alpha6beta1, alpha7beta1 and alpha6beta4 integrins. Matrix Biol 25:189–197CrossRefGoogle Scholar
- Pyke C, Salo S, Rafkiaer E, Romer J, Dano K, Tryggvason K (1995) Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res 55:4132–4139PubMedPubMedCentralGoogle Scholar