Mechanism of anchorage-independency and tumor formation of cancer cells: possible involvement of cell membrane–bound laminin-332

  • Hiroshi KatayamaEmail author


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.


Wound 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.


  1. Aguirre Ghiso JA (2002) Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. Oncogene 21:2513–2524PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bachy S, Letoumeur F, Rousselle P (2008) Syndecan-1 interaction with the LG4/5 domain in laminin-332 is essential for keratinocyte migration. J Cell Physiol 214:238–249PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bernfield M, Kokenyesi R, Kato M, Hinkes MT, Spring J, Gallo RL, Lose EJ (1992) Biology of syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu Rev Cell Biol 8:365–393PubMedCrossRefPubMedCentralGoogle Scholar
  4. Carter WG, Ryan MC, Gahr PJ (1991) Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes. Cell 65:599–610PubMedCrossRefPubMedCentralGoogle Scholar
  5. Carulli S, Beck K, Dayan G, Boulesteix S, Lortat-Jacob H, Rousselle P (2012) Cell surface proteoglycans syndecan-1 and -4 bind overlapping but distinct sites in laminin α3 LG45 protein domain. J Biol Chem 287:12204–12216PubMedPubMedCentralCrossRefGoogle Scholar
  6. Cheng YS, Champliaud MF, Burgeson RE, Marinkovich MP, Yurchenco PD (1997) Self-assembly of laminin isoforms. J Biol Chem 272:31525–31532PubMedCrossRefPubMedCentralGoogle Scholar
  7. Frish SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626CrossRefGoogle Scholar
  8. Frish SM, Vuori K, Ruoslahti E, Chan-Hui PY (1996) Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134:793–799CrossRefGoogle Scholar
  9. Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285:1028–1032CrossRefGoogle Scholar
  10. Goldfinger LE, Hopkinson SB, DeHart GW, Collawn S, Couchman JR, Jones JC (1999) The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin. J Cell Sci 112:2615–2629PubMedPubMedCentralGoogle Scholar
  11. Guess CM, Quaranta V (2009) Defining the role of laminin-332 in carcinoma. Matrix Biol 28:445–455PubMedPubMedCentralCrossRefGoogle Scholar
  12. Hecker TP, Grammer JR, Gillespie GY, Stewart J Jr, Gladson CL (2002) Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res 62:2699–2707PubMedPubMedCentralGoogle Scholar
  13. Katayama H (2018) Development of psoriasis by continuous neutrophil infiltration into the epidermis. Exp Dermatol 27:1084–1091PubMedCrossRefPubMedCentralGoogle Scholar
  14. Katayama H, Kitagawa S, Masuyama J, Yaoita H (1991) Polymorphonuclear leukocyte-induced detachment of cultured epidermal carcinoma cells from the substratum. J Invest Dermatol 97:941–952CrossRefGoogle Scholar
  15. Katayama H, Hase T, Yaoita H (1994) Detachment of cultured normal human keratinocytes by contact with TNF alpha-stimulated neutrophils in the presence of platelet-activating factor. J Invest Dermatol 103:187–190PubMedCrossRefPubMedCentralGoogle Scholar
  16. 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
  17. Kornberg LJ, Earp HS, Turner CE, Prockop C, Juliano RL (1991) Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci USA 88:8392–8396PubMedCrossRefGoogle Scholar
  18. 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
  19. Lam AT, Li J, Chen AK, Birch WR, Reuveny S, Oh SK (2015) Improved human pluripotent stem cell attachment and spreading on xeno-free laminin-521-coated microcarriers results in efficient growth in agitated cultures. Biores Open Access 4:242–257PubMedPubMedCentralCrossRefGoogle Scholar
  20. Lampe PD, Nguyen BP, Gil S, Usui M, Olerud J, Takada Y, Carter WG (1998) Cellular interaction of integrin alpha3beta1 with laminin 5 promotes gap junctional communication. J Cell Biol 143:1735–1747PubMedPubMedCentralCrossRefGoogle Scholar
  21. Lee BY, Timpson P, Horvath LG, Daly RJ (2015) FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146:132–149PubMedCrossRefPubMedCentralGoogle Scholar
  22. Maatta M, Soini Y, Paakko P, Salo S, Tryggvason K, Autio-Harmainen H (1999) Expression of the laminin gamma2 chain in different histological types of lung carcinoma. A study by immunohistochemistry and in situ hybridization. J Pathol 188:361–368PubMedCrossRefPubMedCentralGoogle Scholar
  23. McLean GW, Carragher NO, Avizienyte E, Evance J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat Rev Cancer 5:505–515PubMedPubMedCentralCrossRefGoogle Scholar
  24. Nguyen BP, Gil SG, Carter WG (2000) Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling. J Biol Chem 275:31896–31907PubMedCrossRefPubMedCentralGoogle Scholar
  25. Nielsen PK, Gho YS, Hoffman MP, Watanabe H, Makino M, Nomizu M, Yamada Y (2000) Identification of a major heparin and cell binding site in the LG4 module of the laminin alpha 5 chain. J Biol Chem 275:14517–14523PubMedCrossRefPubMedCentralGoogle Scholar
  26. 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
  27. Okamoto O, Bachy S, Odenthal U, Bernaud J, Rigal D, Lortat-Jacob H, Smyth N, Rousselle P (2003) Normal human keratinocytes bind to the alpha3LG4/5 domain of unprocessed laminin-5 through the receptor syndecan-1. J Biol Chem 278:44168–44177PubMedCrossRefPubMedCentralGoogle Scholar
  28. 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
  29. Rousselle P, Aumailley M (1994) Kalinin is more efficient than laminin in promoting adhesion of primary keratinocytes and some other epithelial cells and has a different requirement for integrin receptors. J Cell Biol 125:205–214PubMedCrossRefPubMedCentralGoogle Scholar
  30. Rousselle P, Beck K (2013) Laminin 332 processing impacts cellular behavior. Cell Adh Migr 7:122–134PubMedPubMedCentralCrossRefGoogle Scholar
  31. Rousselle P, Lunstrum GP, Keene DR, Burgeson RE (1991) Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol 114:567–576PubMedCrossRefPubMedCentralGoogle Scholar
  32. Ruoslahti E (1989) Proteoglycans in cell regulation. J Biol Chem 264:13369–13372PubMedPubMedCentralGoogle Scholar
  33. Ruoslahti E, Yamaguchi Y (1991) Proteoglycans as modulators of growth factor activities. Cell 64:867–869PubMedCrossRefPubMedCentralGoogle Scholar
  34. Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT (1992) pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci USA 89:5192–5196PubMedCrossRefPubMedCentralGoogle Scholar
  35. Sigle RO, Gill SG, Bhattacharya M, Ryan MC, Yang TM, Brown TA, Boutaud A, Miyashita Y, Olerud J, Carter WG (2004) Globular domains 4/5 of the laminin alpha3 chain mediate deposition of precursor laminin 5. J Cell Sci 117:4481–4494PubMedCrossRefPubMedCentralGoogle Scholar
  36. Tran M, Rousselle P, Nokelainen P, Tallapragada S, Nguyen NT, Fincher EF, Marinkovich P (2008) Targeting a tumor-specific laminin domain critical for human carcinogenesis. Cancer Res 68:2885–2894PubMedCrossRefPubMedCentralGoogle Scholar
  37. Tzu J, Marinkovich MP (2008) Bridging structure with function: structural, regulatory, and developmental role of laminins. Int J Biochem Cell Biol 40:199–214PubMedCrossRefPubMedCentralGoogle Scholar
  38. Utani A, Nomizu M, Matsuura H, Kato K, Kobayashi T, Takeda U, Aota S, Nielsen PK, Shinkai H (2001) A unique sequence of the laminin alpha 3 G domain binds to heparin and promotes cell adhesion through syndecan-2 and -4. J Biol Chem 276:28779–28788PubMedCrossRefPubMedCentralGoogle Scholar
  39. Yoon H, Dehart JP, Murphy JM, Lim ST (2015) Understanding the roles of FAK in cancer: inhibitors, genetic models, and new insights. J Histochem Cytochem 63:114–128PubMedCrossRefPubMedCentralGoogle Scholar
  40. Yurchenco PD (2011) Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol 3:a004911PubMedPubMedCentralCrossRefGoogle Scholar
  41. Yurchenco PD, Cheng YS (1993) Self-assembly and calcium-binding sites in laminin. A three-arm interaction model. J Biol Chem 268:17286–17299PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Katayama Dermatology ClinicMaebashiJapan

Personalised recommendations