Cancer and Metastasis Reviews

, Volume 14, Issue 3, pp 219–228 | Cite as

The α6β1 and α6β4 integrins in human prostate cancer progression

  • Anne E. Cress
  • Isaac Rabinovitz
  • Weiguo Zhu
  • Ray B. Nagle


Prostatic secretions are formed by glands composed of basal and luminal cells and surrounded by a basal lamina. The normal basal cells express several integrins (extracellular matrix receptors) including alpha 2, 3, 4, 5, 6, v, beta 1 and beta 4. These integrin units are polarized at the base of the cells adjacent to the basal lamina. The integrin alpha 6 beta 4 is associated with hemidesmosomal-like structures.

The natural history of prostate cancer involves the presence of prostatic intraepithelial neoplasia (PIN) lesions (considered precursor lesions), carcinomain situ and invasive carcinoma. Hemidesmosomal proteins and the α3β1 and α6β1 integrins (laminin receptors) are retained in the early PIN lesions. Expression of the integrins α2, α4, α5, αv and β4 is lost in carcinoma. The α3β1 and α6β1 integrins remain associated with invasive carcinoma, the latter being predominant. Integrin expression in carcinoma is diffuse in the plasma membrane and not restricted to the basal aspects of the cell. The α6β1 integrin is fully functional as judged by an ability to adhere to laminin and contains the wild type α6A cytoplasmic signaling domain. The α6β1 integrin is a leading candidate for conferring the invasive phenotype in prostatic carcinoma.

Tumor cells with high expression of α6 integrin are more invasive when tested in a SCID mouse model system. Following intraperitoneal injection, the human tumor cells invade the mouse diaphragm and move through the muscle on the surface of the laminin coated muscle cells. Our current working hypothesis is that the production of α6β1 and laminin in human tumor cells contributes to the invasive phenotype. Invasion could occur on the surfaces of laminin coated structures such as the nerves, blood vessels or muscle and account for the known patterns of human prostate tumor progression. Blockage of the expression or function of α6β1 or laminin or preventing the loss of β4 would be essential steps in confining the carcinoma to the prostate gland where conventional treatment has already proven effective.

Key words

prostatic neoplasia integrin neoplastic invasion laminin hemidesmosome 


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  1. 1.
    Boring CC, Squires TS, Tong T, Montgomery S: Cancer statistics, 1994. Ca: a Cancer Journal for Clinicians 44: 4–26, 1994Google Scholar
  2. 2.
    Partin AW, Yoo J, Carter HB, Pearson JD, Chan DW, Epstein JI, Walsh PC: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 150: 110–114, 1993Google Scholar
  3. 3.
    Petein M, Michel P, Van Velthoven R: Morphonuclear relationship between prostatic intraepithelial neoplasia and cancers assessed by digital cell image analysis. Am J Clin Pathol 96: 628–634, 1991Google Scholar
  4. 4.
    Bostwick DG: Prostatic intraepithelial neoplasia (PIN). Urology (Suppl) 6: 16–22, 1989Google Scholar
  5. 5.
    Nagle RB, Brawer MK, Kittelson J, Clark V: Phenotypic relationships of prostatic intraepithelial neoplasia to invasive prostatic carcinoma. Am J Pathol 138: 119–128, 1991Google Scholar
  6. 6.
    Verhagen APM, Rameakers FCS, Aalders TW: Colocalization of basal and luminal cell-type cytokeratins in human prostate cancer. Cancer Res 52: 6182–6187, 1992Google Scholar
  7. 7.
    Bonkhoff H, Wernert N, Dhom G, Remberger K: Basement membranes in fetal, adult normal, hyperplastic and neoplastic human prostate. Virchows Arch A Pathol Anat Histopathol 418: 375–381, 1991Google Scholar
  8. 8.
    Bonkhoff H, Wernert N, Dhom G, Remberger K: Distribution of basement membranes in primary and metastatic carcinomas of the prostate. Human Path 23: 934–939, 1992Google Scholar
  9. 9.
    Nagle RB, Hao J, Knox JD, Dalkin BL, Clark V, Cress AE: Expression of hemidesmosomal and extracellular matrix proteins by normal and malignant human prostate tissue. Am J Path 146: 1498–1507, 1995Google Scholar
  10. 10.
    Nagle RB, Cress AE, Bowden GT: Epithelial stromal relationships in the prostate and their role in prostate tumor progression. Adv Pathol and Lab Med, in press: 1995Google Scholar
  11. 11.
    Knox JD, Cress AE, Clark V, Manriquez L, Affinito KS, Dalkin BL, Nagle RB: Differential expression of extracellular matrix molecules and the alpha 6-integrins in the normal and neoplastic prostate. Am J Pathol 145: 167–174, 1994Google Scholar
  12. 12.
    Murphy GP, Busch C, Abrahamsson PAet al.: Histopathology of localized prostate cancer. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12–13, 1993Google Scholar
  13. 13.
    Hostetter AL, Pedersen KV, Gustafsson BL, Manson JC, Boeryd BR: Diagnosis and localization of prostate carcinoma by fine-needle aspiration cytology and correlation with histologic whole-organ sections after radical prostatectomy. Am J Clin Path 94: 693–697, 1990Google Scholar
  14. 14.
    Epstein JI, Carmichael MJ, Pizov G, Walsh PC: Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term followup. J Urol 150: 135–141, 1993Google Scholar
  15. 15.
    Lee SE, Currin SM, Paulson DF, Walther PJ: Flow cytometric determination of ploidy in prostatic adenocarcinoma: a comparison with seminal vesicle involvement and histopathological grading as a predictor of clinical recurrence. J Urol 140: 769–774, 1988Google Scholar
  16. 16.
    Hering F, Schmid HP, Graber P: Influence of microinvasion of the capsule and/or micrometastasis of regional lymph nodes on disease free survival after radical prostatectomy. Ann Urol (Paris) 28: 196–201, 1994Google Scholar
  17. 17.
    Kovi J, Jackson MA, Heshmat MY: Ductal spread in prostatic carcinoma. Cancer 56: 1566–1573, 1985Google Scholar
  18. 18.
    Villers AA, McNeal JE, Freiha FS, Stamey TA: Development of prostatic carcinoma. Morphometric and pathologic features of early stages. Acta Oncol 30: 145–151, 1991Google Scholar
  19. 19.
    Villers A, McNeal JE, Redwine EA, Freiha FS, Stamey TA: The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 142: 763–769, 1989Google Scholar
  20. 20.
    Hamper UM, Sheth S, Walsh PC, Holtz PM, Epstein JI: Carcinoma of the prostate: value of transrectal sonography in detecting extension into the neurovascular bundle. Am J Roent 155: 1015–1019, 1990Google Scholar
  21. 21.
    McNeal JE, Villers AA, Redwine EA, Freiha FS, Stamey TA: Histologic-differentiation, cancer volume, and pelvic lymph node metastasis in adenocarcinoma of the prostate. Cancer 66: 1225–1233, 1990Google Scholar
  22. 22.
    Ware JL: Prostate cancer progression. Implications of histopathology. Am J Pathol 145: 983–993, 1994Google Scholar
  23. 23.
    Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992Google Scholar
  24. 24.
    Juliano RL, Haskill S: Signal transduction from the extracellular matrix. J Cell Biol 120: 577–585, 1993Google Scholar
  25. 25.
    Damsky CH, Werb Z: Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol 4: 772–781, 1992Google Scholar
  26. 26.
    Damsky C, Tremble P, Werb Z: Signal transduction via the fibronectin receptor: do integrins regulate matrix remodeling? Matrix Suppl 1: 184–191, 1992Google Scholar
  27. 27.
    Damsky C, Sutherland A, Fisher S: Extracellular matrix 5: adhesive interactions in early mammalian embryogenesis, implantation, and placentation. Faseb J 7: 1320–1329, 1993Google Scholar
  28. 28.
    Kurpakus MA, Quaranta V, Jones JC: Surface relocation of alpha 6 beta 4 integrins and assembly of hemidesmosomes in anin vitro model of wound healing. J Cell Biol 115: 1737–1750, 1991Google Scholar
  29. 29.
    Cooper HM, Tamura RN, Quaranta V: The major laminin receptor of mouse embryonic stem cells is a novel isoform of the alpha 6 beta 1 integrin. J Cell Biol 115: 843–850, 1991Google Scholar
  30. 30.
    Gotwals PJ, Paine-Saunders SE, Stark KA, Hynes RO: Drosophila integrins and their ligands. Curr Opin Cell Biol 6: 734–739, 1994Google Scholar
  31. 31.
    Zusman S, Grinblat Y, Yee G, Kafatos FC, Hynes RO: Analyses of PS integrin functions during Drosophila development. Development 118: 737–750, 1993Google Scholar
  32. 32.
    Yang JT, Rayburn H, Hynes RO: Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119: 1093–10105, 1993Google Scholar
  33. 33.
    George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO: Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119: 1079–1091, 1993Google Scholar
  34. 34.
    Bonkhoff H, Stein U, Remberger K: Differential expression of alpha 6 and alpha 2 very late antigen integrins in the normal, hyperplastic, and neoplastic prostate: simultaneous demonstration of cell surface receptors and their extracellular ligands. Hum Pathol 24: 243–248, 1993Google Scholar
  35. 35.
    Albelda SM: Role of integrins and other cell adhesion molecules in tumor progression and metastasis. [Review]. Laboratory Investigation 68: 4–17, 1993Google Scholar
  36. 36.
    Dedhar S, Saulnier R, Nagle R, Overall CM: Specific alterations in the expression of alpha 3 beta 1 and alpha 6 beta 4 integrins in highly invasive and metastatic variants of human prostate carcinoma cells selected byin vitro invasion through reconstituted basement membrane. Clin Exp Metastasis 11: 391–400, 1993Google Scholar
  37. 37.
    Witkowski CM, Rabinovitz I, Nagle RB, Affinito KS, Cress AE: Characterization of integrin subunits, cellular adhesion and tumorgenicity of four human prostate cell lines. J Cancer Res Clin Oncol 119: 637–644, 1993Google Scholar
  38. 38.
    Korhonen M, Laitinen L, Ylanne J, Koukoulis GK, Quaranta V, Juusela H, Gould VE, Virtanen I: Integrin distributions in renal cell carcinomas of various grades of malignancy. Am J Pathol 141: 1161–1171, 1992Google Scholar
  39. 39.
    Arihiro K, Inai K, Kurihara K, Takeda S, Khatun N, Kuroi K, Toge T: A role of VLA-6 laminin receptor in invasion of breast carcinoma. Acta Pathologica Japonica 43: 662–669, 1993Google Scholar
  40. 40.
    D'Ardenne AJ, Richman PI, Horton MA, Mcaulay AE, Jordan S: Co-ordinate expression of the alpha-6 integrin laminin receptor sub-unit and laminin in breast cancer. J Pathol 165: 213–220, 1991Google Scholar
  41. 41.
    Rossen K, Dahlstrom KK, Mercurio AM, Wewer UM: Expression of the alpha 6 beta 4 integrin by squamous cell carcinomas and basal cell carcinomas: possible relation to invasive potential? Acta Derm Venereol (Stockh) 74: 101–105, 1994Google Scholar
  42. 42.
    Weinel RJ, Rosendahl A, Pinschmidt E, Kisker O, Simon B, Santoso S: The α6 integrin receptor in pancreatic carcinoma. Gastroenterology 108: 523–532, 1995Google Scholar
  43. 43.
    Lee EC, Lotz MM, Steele G Jr, Mercurio AM: The integrin alpha 6 beta 4 is a laminin receptor. J Cell Biol 117: 671–678, 1992Google Scholar
  44. 44.
    Niessen CM, Hogervorst F, Jaspars LH, de Melker AA, Delwel GO, Hulsman EH, Kuikman I, Sonnenberg A: The alpha 6 beta 4 integrin is a receptor for both laminin and kalinin. Exp Cell Res 211: 360–367, 1994Google Scholar
  45. 45.
    Sonnenberg A: Integrins and their ligands. Curr Top Micro Immunol 184: 7–35, 1993Google Scholar
  46. 46.
    Shaw LM, Messier JM, Mercurio AM: The activation dependent adhesion of macrophages to laminin involves cytoskeletal anchoring and phosphorylation of the alpha 6 beta 1 integrin. J Cell Biol 110: 2167–2174, 1990Google Scholar
  47. 47.
    Jones JC, Kurpakus MA, Cooper HM, Quaranta V: A function for the integrin alpha 6 beta 4 in the hemidesmosome. Cell Regul 2: 427–438, 1991Google Scholar
  48. 48.
    Hogervorst F, Admiraal LG, Niessen C, Kuikman I, Janssen H, Daams H, Sonnenberg A: Biochemical characterization and tissue distribution of the A and B variants of the integrin alpha 6 subunit. J Cell Biol 121: 179–191, 1993Google Scholar
  49. 49.
    Hierck BP, Thorsteinsdottir S, Niessen CMet al.: Variants of the alpha 6 beta 1 laminin receptor in early murine development: distribution, molecular cloning and chromosomal localization of the mouse integrin alpha 6 subunit [published erratum appears in Cell Adhes Commun 1993 Sept; 1(2): following 190]Google Scholar
  50. 50.
    Potts AJ, Croall DE, Hemler ME: Proteolytic cleavage of the integrin beta 4 subunit. Exp Cell Res 212: 2–9, 1994Google Scholar
  51. 51.
    Goll DE, Thompson VF, Taylor RG, Christiansen JA: Role of the calpain system in muscle growth. Biochimie 74: 225–237, 1992Google Scholar
  52. 52.
    Tamura RN, Rozzo C, Starr L, Chambers J, Reichardt LF, Cooper HM, Quaranta V: Epithelial integrin alpha 6 beta 4: complete primary structure of alpha 6 and variant forms of beta 4. J Cell Biol 111: 1593–1604, 1990Google Scholar
  53. 53.
    Shaw LM, Mercurio AM: Regulation of cellular interactions with laminin by integrin cytoplasmic domains: the A and B structural variants of the alpha 6 beta 1 integrin differentially modulate the adhesive strength, morphology, and migration of macrophages. Molecular Biology of the Cell 5: 679–690, 1994Google Scholar
  54. 54.
    Bronner-Fraser M, Artinger M, Muschler J, Horwitz AF: Developmentally regulated expression of α6 integrin in avian embryos. Development 115: 197–211, 1992Google Scholar
  55. 55.
    Hogervorst F, Kuikman I, van Kessel AG, Sonnenberg A: Molecular cloning of the human alpha 6 integrin subunit. Alternative splicing of alpha 6 mRNA and chromosomal localization of the alpha 6 and beta 4 genes. Eur J Biochem 199: 425–433, 1991Google Scholar
  56. 56.
    Shaw LM, Lotz MM, Mercurio AM: Inside-out integrin signaling in macrophages. Analysis of the role of the alpha 6A beta 1 and alpha 6B beta 1 integrin variants in laminin adhesion by cDNA expression in an alpha 6 integrin-deficient macrophage cell line. J Biol Chem 268: 11401–11408, 1993Google Scholar
  57. 57.
    Powell WB, Knox JD, Navre M, Grogan TM, Kittelson J, Nagle RB, Bowden GT: Expression of the metalloproteinase matrilysin in DU-145 cells increases their invasive potential in severe combined immunodeficient mice. Cancer Res 53: 417–422, 1993Google Scholar
  58. 58.
    Rabinovitz I, Nagle RB, Cress AE: Integrin α6 influences the migratory and invasive phenotype of human prostate carcinoma cellsin vitro andin vivo. Clin Exp Met (in press)Google Scholar
  59. 59.
    Pyke C, Romer J, Kallunki P, Lund LR, Ralfkiaer E, Dano K, 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, 1994Google Scholar
  60. 60.
    Fuchs ME, Brawer MK, Rennels MA, Nagle RB: The relationship of basement membrane to histologic grade of human prostatic carcinoma. Mod Pathol 2: 105–111, 1989Google Scholar
  61. 61.
    Bray D: Cell movements. (1st ed.) New York, Garland Publishing Inc., 1992: pp 406Google Scholar
  62. 62.
    Rabinovitz I, Cress AE, Nagle RB: Biosynthesis and secretion of laminin and S-laminin by human prostate carcinoma cell lines. Prostate 25: 97–107, 1994Google Scholar
  63. 63.
    Catalona WJ: Prostate cancer. Orlando, 1984 (Straton G&, ed.)Google Scholar
  64. 64.
    Mostofi FK, Sesterhenn IA, Davis C Jr: Prostatic carcinoma: problems in the interpretation of prostatic biopsies. Hum Pathol 23(3): 223–241, 1992Google Scholar
  65. 65.
    McNeal JE: Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol 23(3): 258–266, 1992Google Scholar
  66. 66.
    McNeal JE, Villers AA, Redwine EA, Freiha FS, Stamey TA: Capsular penetration in prostate cancer. Significance for natural history. Am J Surg Pathol 14(3): 240–247, 1990Google Scholar
  67. 67.
    Friedrichs K, Ruiz P, Franke F, Gille I, Terpe H, Imhof BA: High expression level of α6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res 55: 901–906, 1995Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Anne E. Cress
    • 1
  • Isaac Rabinovitz
    • 1
  • Weiguo Zhu
    • 1
  • Ray B. Nagle
    • 1
  1. 1.Department of Radiation Oncology and PathologyUniversity of Arizona Cancer CenterTucsonUSA

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