Do adhesive molecules ICAM-1 and VCAM-1 affect the development and course of gastrointestinal tumors?
Czy molekuły adhezyjne ICAM-1 i VCAM-1 wpływają na rozwój i przebieg nowotworów przewodu pokarmowego?
Solid tumors are composed of two compartments: cancerous cells constituting the essential mass of tumor and stromal tumor cells. Tumor cells induce the formation of stroma, which is formed of connective tissue and blood vessels, and protects nutrition and gas exchange of tumor cells. Cell-cell and extracellular matrix-cell interactions are mediated by adhesive molecules (CAMs, cell adhesion molecules) and affect the growth, differentiation and migration of tumor cells (1). Abnormal ICAM expression may underlie in morphological disturbances, loss of cell-to-cell junctions, cytoskeleton disorganization, allowing cancer cells to detach from tumor mass and metastase. The adhesins allow tumor cells to stimulate angiogenesis and affect the formation of a metastase (2). The formation of new vessels is necessary to increase the tumor mass of both primary and metastatic lesions (3). The pre-cancerous state or the site of the secondary tumor focus may be inflammation, which is determined by the chemotactic action of pro-inflammatory cytokines as well as by the presence of adhesion molecules on the activated endothelium (2). Thus, tumor progression and its expansion into distant organs is strongly dependent on adhesion molecules, Numerous studies have shown that the clinical stage of the disease is a key prognostic parameter for the survival and recurrence of cancer (4). This means that the features characteristics for cancer cells such as the ability to survive, growth and forming metastatic leasions affect the overall survival of cancer patients, including esophageal, gastric and colorectal cancers.
The studies carried out in the last quarter of a century prove that adhesion molecules, on the one hand, participate in various stages of tumor angiogenesis, participate in its progression and metastasis, but on the other hand, adhesins, suppressor gene expression products have anticancer properties.
The aim of this work is to present the current state of knowledge and results of new research on the expression of selected adhesion molecules: ICAM-1 and VCAM-1 in patients with esophageal, gastric and colorectal cancer.
Intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) belong to adhesion molecules from the immunoglobulin superfamily (IgCAM, immunoglobin cell adhesion molecule, IgSf, Immunoglobin Superfamily), to IgCAM system group (5).
ICAM-1 is glycoprotein with 80-114 kDa mass, the gene coding this protein is located on the short arm of chromosome 19 (19p13.2) (6). ICAM-1 occurs on the surface of endothelial cells, epithelial cells, e.g. thymus, fibroblasts, smooth muscle cells, and hematopoietic cells, e.g. on tissue macrophages, lymphoblasts, tonsil dendritic cells, lymph nodes and Peyer’s patches. ICAM-1 plays an important role during a specific and unspecific immune response. ICAM-1 as major ligand for LFA-1 (lymphocyte function antigen 1) is an important factor in the process immunosurveillance (7). Strong ICAM-1 expression on lymphoma cells was demonstrated during transplant rejection and atherosclerotic lesions (8-10). ICAM-1 is a receptor for erythrocytes infected with Plasmodium falciparum, rhinoviruses, as well as some neurotrophic viruses, e.g. West Nile virus, Semliki Forest virus (SMV) and others (11, 12).
In the last decade, the relationship between the inflammatory process, insulin resistance, and disorders of carbohydrate metabolism and hypertension has been proven. The Salmenniemi study conducted on the obese adult group confirmed the relationship between ICAM-1 concentration and the occurrence of metabolic syndrome (13).
The vascular cell adhesion molecule 1 (VCAM-1) is a transmembrane glycoprotein of 110 kDa mass, made of 739 amino acids. The VCAM-1 coding gene is located on the short arm of chromosome 1 (1p21.2) (14). VCAM-1 expression induces proinflammatory reaction: IL-1, TNF-α or IFN-γ and lipopolysaccharides (LPS), mechanical factors – disturbed blood flow, and reactive oxygen species (ROS), lower antioxidants, ω-3 acids and nitric oxide. In 1990, VLA-4 (very late activation antigen-4) was identified, the first VCAM-1 ligand mediating B-cell adhesions in germinal centers (15). VCAM-1 was shown to be involved in the pathogenesis of autoimmune diseases, cardiovascular disease and infections (16). The main task of VCAM-1 is to control the movement of leukocytes, (with the exception of neutrofils on which VLA-4 is absent) across the endothelial barrier. Under the influence of proinflammatory cytokines, endothelial cells increase the expression of VCAM-1, which promotes adherence of monocytes to endothelial cells and is necessary in their migration. VCAM-1, which is absent at the resting endothelium cells, is detectable on dendritic cells of the lymph nodes, macrophages, bone marrow fibroblasts as well as on tumor cells, e.g. in acute lymphoblastic leukemia and acute myeloblastic leukemia, and in some central nervous system tumors (17).
The involvement of adhesins in the pathogenesis of cancer and metastasis was the basis for their use in diagnostics and prognosis of cancers of lung, breast, genitourinary system, melanoma, pancreas and gastrointestinal tract. The combination of ICAM-1 on a tumor cell with LFA-1 on the surface of T lymphocytes results in an increase in their cytotoxic activity and sensitivity of tumor cells to lymphocyte-dependent cytotoxicity (18). It has been demonstrated that prostaglandin E2, produced by tumor stromal cells, inhibits the expression of ICAM-1 and thus reduces the cytotoxic effect of T lymphocytes (19). Such ICAM-1 activity could justify the results of research in breast, gastric and colorectal cancers, according to which an increase in ICAM-1 expression on cancer cells correlated with a better prognosis (20).
On the other hand, Schröder’s and Rosette’s observations showed a positive correlation between the expression of ICAM-1 and a more aggressive phenotype and greater metastatic potential in breast cancer (21, 22). Usami study in oral squamous cell carcinoma (SCC) have shown that ICAM-1 was expressed predominantly at the invasive front area of tongue SCC and correlated with invasion, lymph node metastasis and increased blood and lymphatic vessel density of the tongue SCC. Increased ICAM-1 expression in tongue SCC was correlated with increased macrophage infiltration within SCC nests. These findings indicate that ICAM-1 plays an important role in tongue SCC progression, which may result from the SCC-cell activity, angiogenic activity, lymphangiogenic activity and macrophage/SCC-cell adhesion (23).
Gumbinger BM: Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 1996; 84: 345-357.
Arya M, Patel HR: Expanding role of chemokines and their receptors in cancer. Expert Rev Anticancer Ther 2003; 3: 749-752.
Gulubova MV: Expression of cell adhesion molecules, their ligands and tumour necrosis factor alpha in the liver of patients with metastatic gastrointestinal carcinomas. Histochem J 2002; 34: 67-77.
Alexiou D, Karayiannakis AJ, Syrigos KN et al.: Serum levels of E-selectin, ICAM-1 and VCAM-1 in colorectal cancer patients: correlations with clinicopathological features, patient survival and tumour surgery. Eur J Cancer 2001; 37: 2392-2397.
Isacke CM, Horton MA: The adhesion molecules facts book. Academic Press 2000: 7-33.
Frick C, Odermatt A, Zen K et al.: Interaction of ICAM-1 with β2-integrin CD11c/CD18: Characterization of a peptide ligand that mimics a putative binding site on domain D4 of ICAM-1. Eur J Immunol 2005; 35: 3610-3621.
Schellhorn M, Haustein M, Frank M et al.: Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Oncotarget 2015; 6: 39342-39356.
Dal-Bo M, Bertoni F, Forconi F et al.: Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance. J Transl Med 2009; 7: 76.
Berger JS, Ballantyne CM, Davidson MH et al.: Peripheral artery disease, biomarkers, and darapladib. Am Heart J 2011; 161: 972-978.
Galkina E, Ley K: Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27: 2292-2301.
Drescher KM, Zoecklein LJ, Rodriguez M: ICAM-1 is crucial for protection from TMEV-induced neuronal damage but not demyelination. J Neurovirol 2002; 8(5): 452-458.
Sharma A, Bhomia M, Honnold SP et al.: Role of adhesion molecules and inflammation in Venezuelan equine encephalitis virus infected mouse brain. Virol J 2011; 8: 197.
Salmenniemi U, Ruotsalainen E, Pihlajamäki J et al.: Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines and adhesion molecules in subjects with metabolic syndrome. Circulation 2004; 110: 3842-3848.
Cybulsky MI, Fries JW, Williams AJ et al.: Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene. Proc Natl Acad Sci U S A 1991; 88: 7859-7863.
Freedman AS, Munro JM, Rice GE et al.: Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110. Science 1990; 249: 1030-1033.
Allavena R, Noy S, Andrews M et al.: CNS elevation of vascular and not mucosal addressin cell adhesion molecules in patients with multiple sclerosis. Am J Pathol 2010; 176: 556-562.
Zarnescu O, Brehar FM, Bleotu C et al.: Co-localization of PCNA, VCAM-1 and caspase-3 with nestin in xenografts derived from human anaplastic astrocytoma and glioblastoma multiforme tumor spheres. Micron 2011; 42: 793-800.
Staunton DE, Dustin ML, Erickson HP et al.: The arrangement of the immunoglobulin-like domains of ICAM- 1 and the binding sites for LFA-1 and rhinovirus. Cell 1990; 61: 243-254.
Basingab FS, Ahmadi M, Morgan DJ: IFN-Dependent Interactions between ICAM-1 and LFA-1 Counteract Prostaglandin E2-Mediated Inhibition of Antitumor CTL Responses. Cancer Immunol Res 2016; 4: 400-411.
Tachimori A, Yamada N, Satake Y et al.: Upregulation of ICAM-1 gene expression inhibits tumor growth and liver metastasis in colorectal carcinoma. Eur J Cancer 2005; 41: 1802-1810.
Schröder C, Witzel I, Müller V et al.: Prognostic value of intercellular adhesion molecule (ICAM)-1 expression in breast cancer. J Cancer Res Clin Oncol 2011; 137(8): 1193-1201.
Rosette C, Roth RB, Oeth P et al.: Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis 2005; 26: 943-950.
Usami Y, Ishida K, Sato S et al.: Intercellular adhesion molecule-1 (ICAM-1) expression correlates with oral cancer progression and induces macrophage/cancer cell adhesion. Int J Cancer 2013; 133: 568-579.
Michael A, Jones JL: Jekyll and Hyde: The role of the microenvironment on the progression of cancer. J Pathol 2011; 223: 162-176.
Qian BZ, Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell 2010; 141: 39-51.
Solinas G, Germano G, Mantovani A et al.: Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 2009; 86: 1065-1073.
Roland C, Dineen SP, Toombs J et al.: Tumor derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts. Exp Biol Med 2010; 235: 263-269.
Komohara Y, Horlad H, Ohnishi K et al.: Importance of direct macrophage – tumor cell interaction on progression of human glioma. Cancer Sci 2012; 103: 2165272.
Zheng Y, Cai Z, Wang S et al.: Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 2009; 114: 3625-3628.
Seth R, Raymond FD, Makgoba MW: Circulating ICAM1 isoforms: Diagnostic prospects for inflammatory and immune disorders. Lancet 1991; 338: 8384.
Zhang GJ, Adachi I: Serum levels of soluble intercellular adhesion molecule-1 and E-selectin in metastatic breast carcinoma: correlation with clinicopathological features and prognosis. Int J Oncol 1999; 14: 71-77.
Kitagawa T, Matsumoto K, Iriyama K: Serum cell adhesion molecules in patients with colorectal cancer. Surg Today 1998; 28: 262-267.
Jublanc C, Beaudeux JL, Aubart F et al.: Serum levels of adhesion molecules ICAM-1 and VCAM-1 and tissue inhibitor of metalloproteinases, TIMP-1, are elevated in patients with autoimmune thyroid disorders: Relevance to vascular inflammation. Nutr Metab Cardiovasc Dis 2011; 21: 817-822.
Byrne GJ, Bundred NJ: Surrogate markers of tumoral angiogenesis. Int J Biol Markers 2000; 15: 334-339.
Wu TC: The role of vascular cell adhesion molecule-1 in tumor immune evasion. Cancer Res 2007; 67: 6003-6006.
Ding YB, Chen GY, Xia JG et al.: Association of VCAM-1 overexpression with oncogenesis, tumor angiogenesis and metastasis of gastric carcinoma. World J Gastroenterol 2003; 9(7): 1409-1414.
Chen Q, Zhang XH, Massague J: Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell 2011; 20: 538-549.
Cao H, Zhang Z, Zhao S et al.: Hydrophobic interaction mediating self-assembled nanoparticles of succinobucol suppress lung metastasis of breast cancer by inhibition of VCAM-1 expression. J Control Release 2015; 205: 162-171.
Chen Q, Massague J: Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis. Clin Cancer Res 2012; 18: 5520-5525.
Maimaiti Y, Wang C, Mushajiang M et al.: Overexpression of VCAM-1 is correlated with poor survival of patients with breast cancer. Int J Clin Exp Pathol 2016; 9(7): 7451-7457.
Alexiou D, Karayiannakis AJ, Syrigos KN et al.: Clinical significance of serum levels of E-selectin, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in gastric cancer patients. Am J Gastroenterol 2003; 98: 478-485.
Alexiou D, Karayiannakis AJ, Syrigos KN et al.: Serum levels of E-selectin, ICAM-1 and VCAM-1 in colorectal cancer patients: correlations with clinicopathological features, patient survival and tumor surgery. Eur J Cancer 2001; 37: 2392-2397.
O’Hanlon DM, Fitzsimons H, Lynch J et al.: Soluble adhesion molecules (E-selectin, ICAM-1 and VCAM-1) in breast carcinoma. Eur J Cancer 2002; 38: 2252-2257.
De Cicco C, Ravasi L, Zorzino L et al.: Circulating levels of VCA Mand MMP-2 may help identify patients with more aggressive prostate cancer. Curr Cancer Drug Targets 2008; 8: 199-206.
Coskun U, Sancak B, Sen I et al.: Serum P-selectin, soluble vascular cell adhesion molecule-I(s-VCAM-I) and soluble intercellular adhesion molecule-I(s-ICAM-I) levels in bladder carcinoma patients with different stages. Int Immunopharmacol 2006; 6: 672-677.
Kayani B, Zacharakis E, Ahmed K et al.: Lymph node metastases and prognosis in esophageal carcinoma – A systematic review. Eur J Surg Oncol 2011; 37: 747-753.
Hosch SB, Izbicki JR, Pichlmeier U et al.: Expression and prognostic significance of immunoregulatory molecules in esophageal cancer. Int J Cancer 1997; 74: 582-587.
Nair KS, Naidoo R, Chetty R: Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol 2005; 58: 343-351.
Liu S, Li N, Yu X et al. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013; 144: 1031-1041.
Tsai ST, Wang PJ, Liou NJ et al.: ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma. PLoS One 2015; 10(11).
Chen M, Huang J, Zhu Z et al.: Systematic review and meta-analysis of tumor biomarkers in predicting prognosis in esophageal cancer. BMC Cancer 2013; 13: 539.
Fujihara T, Yashiro M, Inoue T et al.: Decrease in ICAM-1 expression on gastric cancer cells is correlated with lymph node metastasis. Gastric Cancer 1999; 2: 221-225.
Yashiro M, Sunami T, Hirakawa K: CD54 expression is predictive for lymphatic spread in human gastric carcinoma. Dig Dis Sci 2005; 50: 2224-2230.
Ke JJ, Shao QS, Ling ZQ: Expression of E-selectin, integrin beta1 and immunoglobulin superfamily member in human gastric carcinoma cells and its clinicopathologic significance. World J Gastroenterol 2006; 12: 3609-3611.
Maruo Y, Gochi A, Kaihara A et al.: ICAM-1 expression and the soluble ICAM- 1 level for evaluating the metastatic potential of gastric cancer. Int J Cancer 2002; 100: 486-490.
Jung WC, Jang YJ, Kim JH et al.: Expression of intercellular adhesion molecule-1 and e-selectin in gastric cancer and their clinical significance. J Gastric Cancer 2012; 12(3): 140-148.
Maruo Y, Gochi A, Kaihara A et al.: ICAM-1 expression and the soluble ICAM-1 level for evaluating the metastatic potential of gastric cancer. Int J Cancer 2002; 100(4): 486-490.
Gulubova MV: Expression of cell adhesion molecules, their ligands and tumour necrosis factor alpha in the liver of patients with metastatic gastrointestinal carcinomas. Histochem J 2002; 34: 67-77.
Wimmenauer S, Keller H, Rückauer KD et al.: Expression of CD44, ICAM-1 and N-CAM in colorectal cancer. Correlation with the tumor stage and the phenotypical characteristics of tumor-infiltrating lymphocytes. Anticancer Res 1997; 17: 2395-2400.
Maeda K, Kang SM, Sawada T et al.: Expression of intercellular adhesion molecule-1 and prognosis in colorectal cancer. Oncol Rep 2002; 9: 511-514.
Tachimori A, Yamada N, Sakate Y et al.: Up regulation of ICAM-1 gene expression inhibits tumour growth and liver metastasis in colorectal carcinoma. Eur J Cancer 2005; 41: 1802-1810.
