Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2001 Feb;92(2):184–192. doi: 10.1111/j.1349-7006.2001.tb01081.x

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

Yuumi Kagesato 1,2, Hiroto Mizushima 1, Naohiko Koshikawa 1, Hitoshi Kitamura 3, Hiroyuki Hayashi 3, Nobuo Ogawa 4, Mamoru Tsukuda 2, Kaoru Miyazaki 1,✉
PMCID: PMC5926700  PMID: 11223548

Abstract

Laminin‐5 (LN‐5), an important basement membrane (BM) protein consisting of laminin α3, β3 and γ2 chains, has been suggested to be involved in tumor cell invasion and tissue repair. In this study, the distribution of the LN‐5 subunits in atypical adenomatous hyperplasia (AAH)and different types of adenocarcinomas of the lung was examined by immunohistochemical analysis. In AAH and non‐sclerosing, well‐differentiated adenocarcinomas, the LN γ2 chain was frequently detected along with the continuous BMs. These BMs were also positive for both LNα3 and β3 chains, suggesting that LN‐5 had been deposited. In contrast, the cytoplasmic staining for the LNγ2 chain was frequently observed in tumor cells of sclerosing, well‐differentiated adenocarcinomas, as well as of moderately and poorly differentiated adenocarcinomas, without any evidence of co‐expression of the LNα3 and β3 chains. This staining pattern of the LNγ2 chain was prominent in carcinoma cells invading into interstitial stroma and was associated with the formation of a central scar in the tumor tissues. These results suggest that the LNγ2 chain monomer could be an important indicator of progression of lung adenocarcinoma.

Keywords: Laminin‐5, Laminin γ2 chain, Lung adenocarcinoma, Tumor invasion, Immunohistochemistry

Full Text

The Full Text of this article is available as a PDF (3.5 MB).

References

  • 1.Rousselle , P. , Lunstrum , G. P. , Keene , D. R . and Burgeson , R. E . Kalinin: an epithelium‐specific basement membrane adhesion molecule that is a component of anchoring filaments . J. CellBiol , 114 , 567 – 576 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Carter , W. G. , Ryan , M. C . and Gahr , P. J . Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes . Cell , 65 , 599 – 610 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 3.Verrando , P. , Pisani , A . and Ortonne , J. P . The new basement membrane antigen recognized by the monoclonal antibody GB3 is a large size glycoprotein: modulation of its expression by retinoic acid . Biochim. Biophys. Acta , 942 , 45 – 56 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 4.Miyazaki , K. , Kikkawa , Y. , Nakamura , A. , Yasumitsu , H . and Umeda , M . A large cell‐adhesive scatter factor secreted by human gastric carcinoma cells . Proc. Natl. Acad. Sci. USA , 90 , 11767 – 11771 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Niessen , C. M. , Hogervorst , F. , Jaspars , L. H. , de Melker , A. A. , Delwel , G. O. , Hulsman , E. H. M. , Kuikman , I . and Sonnenberg , A . The alpha 6 beta 4 integrin is a receptor for both laminin and kalinin . Exp. Cell Res. , 211 , 360 – 367 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 6.Rousselle , P. , Keene , D. R. , Ruggiero , F. , Champliaud , M. F. , Rest , M . and Burgeson , R. E . Laminin 5 binds the NC‐1 domain of type VII collagen . J. Cell Biol. , 138 , 719 – 728 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Aberdam , D. , Galliano , M. F. , Vailly , J. , Pulkkinen , L. , Bonifas , J. , Christiano , A. M. , Tryggvason , K. , Uitto , J. , Epstein , E. H. , Jr. , Ortonne , J. P . and Meneguzzi , G . Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/ kalinin (LAMININ‐5) . Nat. Genet. , 6 , 299 – 304 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 8.Pulkkinen , L. , Christiano , A. M. , Gerecke , D. , Wagman , D. W. , Burgeson , R. E. , Pittelkow , M. R . and Uitto , J . A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa . Genomics , 24 , 357 – 360 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 9.Kivirikko , S. , McGrath , J. A. , Baudoin , C. , Aberdam , D. , Ciatti , S. , Dunnill , M. G. , McMillan , J. R. , Eady , R. A. , Ortonne , J. P. , Meneguzzi , G. , Uitto , J . and Christiano , A. M . A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa . Hum. Mol. Genet , 4 , 959 – 962 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10.Kikkawa , Y. , Umeda , M . and Miyazaki , K . Marked stimulation of cell adhesion and motility by ladsin, a laminin‐like scatter factor . J. Biochem. , 116 , 862 – 869 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 11.Kikkawa , Y. , Akaogi , K. , Mizushima , H. , Yamanaka , N. , Umeda , M . and Miyazaki , K . Stimulation of endothelial cell migration in culture by ladsin, a laminin‐5‐like cell adhesion protein . In Vitro Cell. Dev. Biol. Anim. , 32 , 46 – 52 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 12.Mizushima , H. , Miyagi , Y. , Kikkawa , Y. , Yamanaka , N. , Yasumitsu , H. , Misugi , K . and Miyazaki , K . Differential expression of laminin‐5/ladsin subunits in human tissues and cancer cell lines and their induction by tumor promoter and growth factors . J. Biochem. , 120 , 1196 – 1202 ( 1996. ). 9010770 [Google Scholar]
  • 13.Korang , K. , Christiano , A. M. , Uitto , J . and Mauviel , A . Differential cytokine modulation of the genes LAMA3, LAMB3, and LAMC2, encoding the constitutive polypeptides, alpha 3, beta 3, and gamma 2, of human laminin 5 in epidermal keratinocytes . FEBS Lett. , 368 , 556 – 558 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14.Pyke , C. , Rømer , J. , Kallunki , P. , Lund , L. R. , Ralfkiaer , E. , Danø , K . and Tryggvason , K . The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers . Am. J. Pathol. , 145 , 782 – 791 ( 1994. ). [PMC free article] [PubMed] [Google Scholar]
  • 15.Pyke , C. , Salo , S. , Ralfkiær , E. , Rømer , J. , Danø , K . and Tryggvason , K . 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 – 4139 ( 1995. ). [PubMed] [Google Scholar]
  • 16.Soini , Y. , Maatta , M. , Salo , S. , Tryggvason , K . and Autio‐Harmainen , H . Expression of the laminin gamma 2 chain in pancreatic adenocarcinoma . J. Pathol. , 180 , 290 – 294 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 17.Ono , Y. , Nakanishi , Y. , Ino , Y. , Niki , T. , Yamada , T. , Yoshimura , K. , Saikawa , M. , Nakajima , T . and Hirohashi , S . Clinicopathologic significance of laminin‐5 γ2 chain expression in squamous cell carcinoma of the tongue . Cancer , 85 , 2315 – 2321 ( 1999. ). [PubMed] [Google Scholar]
  • 18.Määttä , M. , Soini , Y. , Pääkö , P. , Salo , S. , Tryggvason , K . and Autio‐Harmainen , H . Expression of the laminin gamma 2 chain in different histological types of lung carcinoma. A study by immunohistochemistry and in situ hybridization . J. Pathol. , 188 , 361 – 368 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 19.Tani , T. , Karttunen , T. , Kiviluoto , T. , Kivilaakso , E. , Burgeson , R. E. , Sipponen , P . and Virtanen , I . α6β4 integrin and newly deposited laminin‐1 and laminin‐5 form the adhesion mechanism of gastric carcinoma . Am. J. Pathol. , 149 , 781 – 793 ( 1996. ). [PMC free article] [PubMed] [Google Scholar]
  • 20.Lohi , J. , Oivula , J. , Kivilaakso , E. , Kiviluoto , T. , Fröjdman , K. , Yamada , Y. , Burgeson , R. E. , Leivo , I . and Virtanen , I . Basement membrane laminin‐5 is deposited in colorectal adenomas and carcinomas and serves as a ligand for alphaSbetal integrin . APMIS , 108 , 161 – 172 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 21.Lohi , J. , Leivo , L , Owaribe , K. , Burgeson , R. E. , Franssila , K . and Virtanen , I . Neoexpression of the epithelial adhesion complex antigens in thyroid tumours is associated with proliferation and squamous differentiation markers . J. Pathol. , 184 , 191 – 196 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 22.Sordat , I. , Bosnian , F. T. , Dorta , G. , Rousselle , P. , Aberdam , D. , Blum , A. L . and Sordat , B . Differential expression of laminin‐5 subunits and integrin receptors in human colorectal neoplasia . J. Pathol. , 185 , 44 – 52 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 23.Koshikawa , N. , Moriyama , K. , Takamura , H. , Mizushima , H. , Nagashima , Y. , Yanoma , S . and Miyazaki , K . Overex‐pression of laminin gamma 2 chain monomer in invading gastric carcinoma cells . Cancer Res. , 59 , 5596 – 5601 ( 1999. ). [PubMed] [Google Scholar]
  • 24.Kitamura , H. , Kameda , Y. , Nakamura , N. , Inayama , Y. , Nakatani , Y. , Shibagaki , T. , Ito , T. , Hayashi , H. , Kimura , H . and Kanisawa , M . Atypical adenomatous hyperplasia and bronchoalveolar lung carcinoma. Analysis by mor‐phometry and the expressions of p53 and carcinoembryonic antigen . Am. J. Surg. Pathol. , 20 , 553 – 562 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 25.Slebos , R. J. , Baas , I. O. , Clement , M. J. , Offerhaus , G. J. , Askin , F. B. , Hruban , R. H . and Westra , W. H . p53 alterations in atypical alveolar hyperplasia of the human lung . Hum. Pathol. , 29 , 801 – 808 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 26.Shimosato , Y. , Suzuki , A. , Hashimoto , T. , Nishiwaki , Y. , Kodama , T. , Yoneyama , T . and Kameya , T . Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers . Am. J. Surg. Pathol. , 4 , 365 – 373 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 27.Catusse , C. , Polette , M. , Coraux , C. , Burlet , H . and Birembaut , P . Modified basement membrane composition during bronchopulmonary tumor progression . J. His-tochem. Cytochem. , 48 , 663 – 669 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 28.Travis , W. D. , Colby , T. V. , Corrin , B. , Shimosato , Y. , Brambilla , E. , Collaboration with Sobin, L. H. and Pathologists from 14 Countries. “World Health Organization. International Histological Classification of Tumours . Histological Typing of Lung and Pleural Tumors ,” 3rd Ed. , pp . 28 – 38 ( 1999. ). Springer; , Germany . [Google Scholar]
  • 29.Kitamura , H. , Oosawa , Y. , Kawano , N. , Kameda , Y. , Hayashi , H. , Nakatani , Y. , Udaka , N. , Ito , T . and Miyazaki , K . Basement membrane patterns, gelatinase A and tissue inhibitor of metalloproteinase‐2 expressions, and stromal fibrosis during the development of peripheral lung adeno‐carcinoma . Hum. Pathol , 30 , 331 – 338 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 30.Wayner , E. A. , Gil , S. G. , Murphy , G. R , Wilke , M. S . and Carter , W. G . Epiligrin, a component of epithelial basement membranes, is an adhesive ligand for alpha 3 beta 1 positive T lymphocytes . J. Cell Biol , 121 , 1141 – 1152 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Mizushima , H. , Koshikawa , N. , Moriyama , K. , Takamura , H. , Nagashima , Y. , Hirahara , F . and Miyazaki , K . Wide distribution of laminin‐5 gamma 2 chain in basement membranes of various human tissues . Harm. Res. , 50 ( Suppl. 2 ), 7 – 14 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 32.Akaogi , K. , Okabe , Y. , Sato , J. , Nagashima , Y. , Yasumitsu , H. , Sugahara , K . and Miyazaki , K . Specific accumulation of tumor‐derived adhesion factor in tumor blood vessels and in capillary tube‐like structures of cultured vascular endothelial cells . Proc. Natl. Acad. Set. USA , 93 , 8384 – 8389 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Matsui , K. , Kitagawa , M. , Sugiyama , S . and Yamamoto , K . Distribution pattern of the basement membrane components is one of the significant prognostic correlates in peripheral lung adenocarcinomas . Hum. Pathol. , 26 , 186 – 194 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 34.Nishino , T. , Ishida , T. , Oka , T. , Yasumoto , K . and Sugimachi , K . Prognostic significance of laminin in adeno‐carcinoma of the lung . J. Surg. Oncol. , 43 , 214 – 218 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 35.Watanabe , N. , Nakajima , I. , Abe , S. , Ogura , S. , Isobe , H . and Kawakami , Y . Staining pattern of type IV collagen and prognosis in early stage adenocarcinoma of the lung . J. Clin. Pathol. , 47 , 613 – 615 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Noguchi , M. , Morikawa , A. , Kawasaki , M. , Matsuno , Y. , Yamada , T. , Hirohashi , S. , Kondo , H . and Shimosato , Y . Small adenocarcinoma of the lung. Histologic characteristics and prognosis . Cancer , 75 , 2844 – 2852 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 37.Curran , S . and Murray , G. I . Matrix metalloproteinases in tumour invasion and metastasis . J. Pathol. , 189 , 300 – 308 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 38.Giannelli , G. , Falk‐Marzillier , J. , Schiraldi , O. , Stetler‐Stevenson , W. G . and Quaranta , V . Induction of cell migration by matrix metalloprotease‐2 cleavage of laminin‐5 . Science , 277 , 225 – 228 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 39.Koshikawa , N. , Giannelli , G. , Cirulli , V. , Miyazaki , K . and Quaranta , V . Role of cell surface metalloprotease MT1‐MMP in epithelial cell migration over laminin‐5 . J. Cell Biol. , 148 , 615 – 624 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Hirosaki , T. , Mizushima , H. , Tsubota , Y. , Moriyama , K . and Miyazaki , K . Structural requirement of carboxyl‐termi‐nal globular domains of laminin α3 chain for promotion of rapid cell adhesion and migration by laminin‐5 . J. Biol. Chem. , 275 , 22495 – 22502 ( 2000. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES