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Ito Cell Morphology, α-smooth Muscle Actin and Collagen Type IV Expression in the Liver of Patients with Gastric and Colorectal Tumors

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Abstract

The alteration in sinusoidal collagen type IV occurrence, and myofibroblastic (α-SMA-positive) Ito cellular transformation are described in the liver of patients with malignant gastric and colorectal tumors, using electron microscopy as well as light microscopical and ultrastructural immunohistochemistry. The ultrastructural finding revealed transformation of Ito cells mostly into transitional cells in highly differentiated primary tumors and into transitional and myofibroblast-like cells with expressed changes in the other sinusoidal cells in poorly differentiated tumors. Ito cell numbers increased significantly in the livers of cancer patients. A highly significant statistical association was obtained between Ito cell numbers on the one hand and collagen type IV and α-SMA immunoreactivity on the other hand in the pericentral zone of the liver lobule.

Ultrastructural immunohistochemistry showed increased collagen IV immune deposits in the space of Disse, assembled for the most part around and inside transitional cells. α-SMA immunoreactivity was detected in activated Ito cells diffuse in the lobule, with stronger expression in the intermediate and pericentral zones. It is suggested that stimuli which can influence Ito cell transformation are produced by tumor cells from the primary tumor (TGF-β1, TNF-α, PDGF-β etc.) and from the metastasizing gastric or colorectal tumor cells – matrix metalloproteinase-2 (MMP-2). It is suggested that sinusoidal extracellular matrix deterioration creates a barrier for cancer invasion on the one hand, or possibly facilitates metastasizing by ensurance of matrix for adhesion on the other hand.

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References cited

  • Albini A, Melchiori A, Santi L, Liotta LA, Brown PD, Stetler-Stevenson WG (1991) Tumor cell invasion inhibited by TIMP-2. Rep J Natl Cancer Inst 83: 775-779.

    Google Scholar 

  • Akiyama SK, Olden K, Yamada KM (1995) Fibronectin and integrins in invasion and metastasis. Cancer Metast Rev 14: 173-189.

    Google Scholar 

  • Akiyoshi H, Terada T (1998) Mast cell, myofibroblast and nerve terminal complexes in carbon tetrachloride-induced cirrhotic rat livers. J Hepatol 29: 112-119.

    Google Scholar 

  • Bhathal PS (1972) Presence of modified fibroblasts in cirrhotic livers in man. Pathology 4: 139-144.

    Google Scholar 

  • Bioulac-Sage P, Balabaud C, Dubroca J et al. (1986) Sinusoids and the Disse space in patients with liver diseases. In: Bienvenu J, Grimaud JA, Laurent P eds. Marker Proteins in Inflammation. Berlin, New York: Walter de Gruyter & Co., pp. 417-431.

    Google Scholar 

  • Callea F, Mebis J, Desmet VJ (1982) Myofibroblasts in focal nodular hyperplasia of the liver. Virchows Arch A [Pathol. Anat.] 396: 155-166.

    Google Scholar 

  • Chao C, Lotz MM, Clarke AC, Mercurio AM (1996) A function for the integrin α6β4 in the invasive properties of colorectal carcinoma cells. Cancer Res 56: 4811-4819.

    Google Scholar 

  • Clement B, Grimaud J-A, Campion J-P, Deugnier Y, Guillouzo A (1986) Cell types involved in collagen and fibronectin production in normal and fibrotic human liver. Hepatology 6: 225-234.

    Google Scholar 

  • David, L, Nesland JM, Holm R, Sobrinho-Simoes M (1994) Expression of laminin, collagen IV, fibronectin and type IV collagenase in gastric carcinoma: an immunohistochemical study of 87 patients. Cancer 73: 518-527.

    Google Scholar 

  • Desmouliere A, Tuchweber B, Gabbiani G (1995) Role of myofibroblast differentiation during liver fibrosis. J Hepatol 22(Suppl. 2): 61-64.

    Google Scholar 

  • De Vos R, De Wolf-Peeters C, Van Den Oord JJ, Desmet V (1985) A recommended procedure for ultrastructural immunohistochemistry on small human tissue samples. J Histochem Cytochem 33: 959-964.

    Google Scholar 

  • De Vries TJ, Van Muijen GNP, Ruiter DJ (1996) The plasminogen activation system in tumor invasion and metastasis. Path Res Pract 192: 718-733.

    Google Scholar 

  • Enzan H, Himeno H, Iwamura S et al. (1994) α-Smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carcinoma. Hepatology 19: 895-903.

    Google Scholar 

  • Faouzi S, Le Bail B, Neaud V et al. (1999) Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol 30: 275-284.

    Google Scholar 

  • Flug M, Köpf-Maier P (1995) The basement membrane and its involvement in carcinoma cell invasion. Acta Anat 152: 69-84.

    Google Scholar 

  • Friedl P, Brocker E-B, Zanker KS (1998) Integrins, cell matrix interactions and cell migration strategies: fundamental differences in leukocytes and tumor cells. Cell Adhes Commun 6: 225-236.

    Google Scholar 

  • Gress TM, Menke A, Bachem M et al. (1998) Role of extracellular matrix in pancreatic diseases. Digestion 59: 625-637.

    Google Scholar 

  • Gressner AM (1995) Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Pathol 22(Suppl. 2): 28-36.

    Google Scholar 

  • Gressner AM (1996) Mediators of hepatic fibrogenesis. Hepatogastroenterology 43: 92-103.

    Google Scholar 

  • Gressner AM (1998) The cell biology of liver fibrogenesis-an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res 292: 447-452.

    Google Scholar 

  • Griffini P, Smorenburg SM, Vogels IMC, Tigchelaar W, Van Noorden CJF (1996) Kupffer cells and pit cells are defective in the defense against experimentally induced colon carcinoma metastasis in rat liver. Clin Exp Metast 14: 367-380.

    Google Scholar 

  • Grigioni WF, D'Errico A, Fortunato C et al. (1994) Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane. Modern Pathol 7: 220-225.

    Google Scholar 

  • Gulubova MV (1997a) Carcinoma-associated collagen type III and type IV immune localization and Ito cell transformation indicate tumor-related changes in sinusoids of the human liver. Acta Histochem 99: 325-344.

    Google Scholar 

  • Gulubova MV (1997b) Sinusoidal pit cells' morphology in patients with malignant gastrointestinal tumors non-metastasising in the liver. Savr Med (Bul) 48: 28-32.

    Google Scholar 

  • Gulubova MV, Popov A (1994/95) Sinusoidal changes in extratumoral liver tissue. Report of a case of metastatic liver small cell carcinoma with collagen IV detection and ultrastructural studies. Zentralbl Pathol 140: 443-447.

    Google Scholar 

  • Hanamura N, Yoshida T, Matsumoto E, Kawarada Y, Sakakura T (1997) Expression of fibronectin and tenascin-c mRNA by myofibroblasts, vascular cells and epithelial cells in human colon adenomas and carcinomas. Int J Cancer 73: 10-15.

    Google Scholar 

  • Herbst H, Wege T, Milani S et al. (1997) Tissue inhibitor of metalloproteinase-1 and-2 RNA expression in rat and human liver fibrosis. Am J Pathol 150: 1647-1659.

    Google Scholar 

  • Hida J, Matsuda T, Kitaoka M, Machidera N, Kubo R, Yasutomi M (1994) The role of basement membrane in colorectal cancer invasion and liver metastasis. Cancer 74: 592-598.

    Google Scholar 

  • Horn T, Junge J, Nielsen O, Christoffersen P (1988) Light microscopical demonstration and zonal distribution of parasinusoidal cells (Ito cells) in normal human liver. Virchows Arch A Pathol Anat 413: 147-149.

    Google Scholar 

  • Hsu S, Huang F, Friedman E (1995) Paracrine PDGF-B increases colon cancer growth in vivo. J Cell Physiol 165: 239-245.

    Google Scholar 

  • Humphrey C, Pittman F (1974) A simple methylene blue-azure 2 basic fuchsin stain for epoxy-embedded tissue sections. Stain Technol 49: 9-14.

    Google Scholar 

  • Iredale JP (1996) Matrix turnover in fibrogenesis. Hepatogastroenterology 43: 56-71.

    Google Scholar 

  • Jansen R, Schimmer C, Ackermann R, Somasundaram R, Schuppan D. (1995) Tumor-nekrose-factor-alpha und-beta (TNF-alpha und-beta) binden spezifisch an die leberkollagene typ I, II, IV, V und VI. Z Gastroenterol 33: 34.

    Google Scholar 

  • Johnson SJ (1996) Extracellular matrix proteins and hepatic fibrosis. Hepatogastroenterology 43: 44-55.

    Google Scholar 

  • Johnson SJ, Burr AW, Toole K, Dack CL, Mathew J, Burt AD (1998) Hepatocellular carcinoma. Macrophage and hepatic stellate cell responses during experimental hepatocarcinogenesis. J Gastroenterol Hepatol 13: 145-151.

    Google Scholar 

  • Karakiulakis G, Papanikolaou C, Jankovic SM et al. (1997) Increased type IV collagen-degrading activity in metastases originating from primary tumours of the human colon. Invasion Metastasis 17: 158-168.

    Google Scholar 

  • Kobayashi H, Shinohara H, Takeuchi K et al. (1994) Inhibition of the soluble and tumor cell receptor-bound plasmin by urinary trypsin inhibitor and subsequent effects on tumor cell invasion and metastasis. Cancer Res 54: 844-849.

    Google Scholar 

  • Koukoulis GK, Gould VE, Bhattacharyya A, Gould JE, Howeedy AA, Virtanen I (1991) Tenascin in normal, reactive, hyperplastic and neoplastic tissues: biologic and pathologic implications. Hum Pathol 22: 636-643.

    Google Scholar 

  • Labat-Robert J (1998) Cell-matrix interactions, alterations with aging, involvement in angiogenesis. Pathol Biol 46: 527-533.

    Google Scholar 

  • Liotta LA (1986) Tumor invasion and metastases-role of the extracellular matrix: Rhoads memorial award lecture. Cancer Res 46: 1-7.

    Google Scholar 

  • Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S (1980) Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature (Lond.) 284: 67-68.

    Google Scholar 

  • Madarame T, Nagaoka T, Inomata M et al. (1991) Basement membrane-like structure may play a role in the alteration of endothelial fenestration. In: Wisse E, Knook DL, Mccuskey RS eds. Cells of the Hepatic Sinusoid Vol. 3. The Netherlands, Rijswijk: Kupffer Cell Foundation, pp. 98-101.

    Google Scholar 

  • Mak KM, Lieber CS (1988) Lipocytes and transitional cells in alcoholic liver disease: a morphometric study. Hepatology 8: 1027-1033.

    Google Scholar 

  • Mak KM, Leo MA, Lieber CS (1984) Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells. Gastroenterology 87: 188-200.

    Google Scholar 

  • Mizuno N, Kato Y, Shirota K et al. (1998) Mechanism of initial distribution of blood-borne colon carcinoma cells in the liver. J Hepatol 28: 878-885.

    Google Scholar 

  • Nakamura M, Shibazaki M, Nitta Y, Endo Y (1998) Translocation of platelets into Disse spaces and their entry into hepatocytes in response to lipopolysaccharides, interleukin-1 and tumour necrosis factor: the role of Kupffer cells. J Hepatol 28: 991-999.

    Google Scholar 

  • Olaso E, Santisteban A, Bidaurrazaga J, Gressner AM, Rosenbaum J, Vidal-Vanaclocha F (1997) Tumor-dependent activation of rodent hepatic stellate cells during experimental melanoma metastasis. Hepatology 26: 634-642.

    Google Scholar 

  • Orita H, Korenaga D, Maehara Y, Baba H, Sugimachi K (1993) Laminin distribution patterns are closely related to liver metastasis in gastric cancer. Cancer 71: 1201-1206.

    Google Scholar 

  • Picon A, Gold LI, Wang J, Cohen A, Friedman A (1998) A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor β1. Cancer Epidemiol Biomark Prev 7: 497-504.

    Google Scholar 

  • Pyke C, Kristensen P, Ralfkiaer E et al. (1991) Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells or invasive foci in human colon adenocarcinomas. Am J Pathol 138: 1059-1067.

    Google Scholar 

  • Quondamatteo F, Scherf C, Miosge N, Herken R (1999) Immunohistochemical localization of laminin, nidogen, and type IV collagen during the early development of human liver. Histochem Cell Biol 111: 39-47.

    Google Scholar 

  • Ramadori G (1991) The stellate cell (Ito cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell. Virchows Arch. B Cell Pathol 61: 147-158.

    Google Scholar 

  • Sanjuan X, Fernandez PL, Miguel R et al. (1996) Overexpression of the 67-kD laminin receptor correlates with tumor progression in human colorectal carcinoma. J Pathol 179: 376-380.

    Google Scholar 

  • Schmitt-Gräff A, Krüger S, Bochard F, Gabbiani G, Denk H (1991) Modulation of alpha smooth muscle actin and desmin expression of perisinusoidal cells of normal and diseased human livers. Am J Pathol 138: 1233-1244.

    Google Scholar 

  • Schürch W, Seemayer TA, Gabbiani G (1998) The myofibroblast. A quarter century after its discovery. Am J Surg Pathol 22: 141-147.

    Google Scholar 

  • Smorenburg SM, Griffini P, Tiggelman AMBC, Moorman AFM, Boers W, Van Noorden CJF (1996) α2-Macroglobulin is mainly produced by cancer cells and not by hepatocytes in rats with colon carcinoma metastases in liver. Hepatology 23: 560-570.

    Google Scholar 

  • Somasundaram R, Ackermann R, Schmid M, Obsterling C, Riecken EO, Schuppan D (1995) Interaktion von kollagenen mit plattchenwachstumsfaktoren (PDGF)-ein mechanismus fur das fortschreiten einer leberfibrose? Z Gastroenterol 33: 37-38.

    Google Scholar 

  • Sordat I, Bosman FT, Dorta G et al. (1998) Differential expression of laminin-5 subunits and integrin receptors in human colorectal neoplasia. J Pathol 185: 44-52.

    Google Scholar 

  • Stoward PJ, Pearse AGE (1991) Histochemistry. Theoretical and Applied Vol 3, 4th edn. New York: Churchill Livingstone.

    Google Scholar 

  • Stoyanova II, Gulubova MV (1998) Peptidergic nerve fibres in the human liver. Acta Histochem 100: 245-256.

    Google Scholar 

  • Stoyanova I, Chouchkov C, Scheuermann DW (1997) Immuno cytochemical localization of the neurons in the superior mesenteric ganglion innervating the small intestine of the cat. Ann Anat 179: 517-523.

    Google Scholar 

  • Sundberg C, Ljungstrom M, Lindmark G, Gerdin B, Rubin K (1993) Microvascular pericytes express PDGF β-receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol 143: 1377-1388.

    Google Scholar 

  • Sztark F, Dubroca J, Latry P, Quinton A, Balabaud C, Bioulac-sage P (1986) Perisinusoidal cells in patients with normal liver histology. A morphometric study. J Hepatol 2: 358-369.

    Google Scholar 

  • Tani T, Karttunen T, Kiviluoto T et al. (1996) α6β4 Integrin and newly deposited laminin-1 and laminin-5 form the adhesion mechanism of gastric carcinoma. Am J Pathol 149: 781-793.

    Google Scholar 

  • Terada T, Makimoto K, Terayama N, Suzuki Y, Nakanuma Y (1996) Alpha-smooth muscle actin positive stromal cells in cholangiocarcinomas, hepatocellular carcinomas and metastatic liver carcinomas. J Hepatol 24: 706-712.

    Google Scholar 

  • Terayama N, Terada T, Nakanuma Y (1996) An immunohistochemical study of tumour vessels in metastatic liver cancers and the surrounding liver tissue. Histopathology 29: 37-43.

    Google Scholar 

  • Tsuchiya Y, Endo Y, Sato H et al. (1994) Expression of type IV collagenases in human tumor cell lines that can form liver colonies in chick embryos. Int J Cancer 56: 46-51.

    Google Scholar 

  • Van Driel BEM, Van Noorden CJF (1999) Oxygen intensitivity of the histochemical assay of glucose-6-phosphate dehydrogenase activity for the discrimination between nonmalignant and malignant cells. J Histochem Cytochem 47: 575-582.

    Google Scholar 

  • Van Driel BEM, Valet GK, Lyon H, Hansen U, Song, J-Y, Van Noorden CJF (1999) Prognostic estimation of survival of colorectal cancer patients with the quantitative histochemical assay of G6PDH activity and the multiparameter classification program CLASSIF1. Cytometry 38: 176-183.

    Google Scholar 

  • Van Nhieu JT, Brocheriou I, Preaux A-M et al. (1998) Myofibroblasts and hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol 29: 120-128.

    Google Scholar 

  • Van Noorden CJF, Jonges TGN, Van Marle J et al. (1998) Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B. Clin Exp Metastasis 16: 159-167.

    Google Scholar 

  • Van Noorden CJF, Meade-Tollin LC, Bosman FT (1998) Metastasis. The spread of cancer cells to distant sites implies a complex series of cellular abnormalities caused, in part, by genetic abberations. Am Sci 86: 130-141.

    Google Scholar 

  • Vlaykova T, Muhonen T, Hahka-Kemppinen M, Pyrhonen S, Jekunen A (1997) Vascularity and prognosis of metastatic melanoma. Int J Cancer 74: 326-329.

    Google Scholar 

  • Wake K (1999) Cell-cell organization and functions of 'sinusoids' in liver microcirculation system. J Electron Microsc 48: 89-98.

    Google Scholar 

  • Watson SA, Morris TM, Robinson G, Crimmin MJ, Brown PD, Hardcastle JD (1995) Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res 55: 3629-3633.

    Google Scholar 

  • Wernert N (1997) The multiple roles of tumour stroma. Virchows Arch 430: 433-443.

    Google Scholar 

  • Wewer UM, Albrechtsen R (1992) Carcinoma-associated perisinusoidal laminin may signal tumor cell metastasis to the liver. Virchows Arch A Pathol Anat Histopathol 421: 87-93.

    Google Scholar 

  • Wisse E, Asosingh K, Braet F, Luo D, De Zanger R (1997) Growth enhancement of CC531 colon carcinoma cells in vitro by (activated) fat-storing cells or extracellular matrix. In: Wisse E, Knook DL, Balabaud C eds. Cells of the Hepatic Sinusoid.Vol. 6. The Netherlands: Rijswijk: Kupffer Cell Foundation, pp. 441-444.

    Google Scholar 

  • Yamaoka K, Nouchi T, Marumo F, Sato C (1993) α-Smooth-muscle actin expression in normal and fibrotic human livers. Dig Dis Sci 38: 1473-1479.

    Google Scholar 

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  1. Department of General and Clinical Pathology, Medical Faculty, Thracian University, Armeiska str. 16-E-2, Stara Zagora, 6003, Bulgaria

    Maya Vladova Gulubova

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Gulubova, M.V. Ito Cell Morphology, α-smooth Muscle Actin and Collagen Type IV Expression in the Liver of Patients with Gastric and Colorectal Tumors. Histochem J 32, 151–164 (2000). https://doi.org/10.1023/A:1004043206422

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