Background Inflammatory reactions, known to promote tumor growth and invasion, have been found associated with colorectal carcinoma (CRC). Macrophages are the chief component of the inflammatory infiltration that occurs early in the progression from non-invasive to malignant tumor, with a switch from the pro-inflammatory phenotype to the tumor-promoting phenotype. Tumor and stroma are additional sources of inflammation-related molecules. The study aimed to evaluate, during colorectal carcinogenesis from benign to malignant phases: i) the trend of serum levels of IL-8, IL-6, TGFβ1, VEGF and MMPs; ii) the parallel trend of CRP serum levels; iii) derangement of the principal TGFβ1 receptors (TGFβ1RI/RII) in tumor tissues. Methodology/Principal findings 96 patients with colon adenomas or CRC at different stages of progression, and 17 controls, were recruited. Serum IL-8, IL-6, TGFβ1, VEGF, MMPs and CRP levels were analyzed before endoscopy or surgery. TGFβ1 receptors were evaluated in adenoma biopsies and surgically-removed colorectal adenocarcinomas. Serum levels of IL-8 in adenocarcinoma patients were increased from stage II, when also the enzymatic activity of MMP-9 increased. Of note, the increasing trend of the two serum markers was found significantly correlated. Trend of serum CRP was also very similar to that of IL-8 and MMP-9, but just below statistical significance. TGFβ1 levels were lower at stage III CRC, while IL-6 and VEGF levels had no significant variations. In tissue specimens, TGFβ1 receptors were already absent in about 50% of adenomas, and this percentage of missing receptors markedly increased in CRC stages III and IV. Conclusions Combined quantification of serum IL-8, MMP-9 and CRP, appears a reliable and advanced index of inflammation-related processes during malignant phase of colorectal carcinogenesis, since these molecules remain within normal range in colorectal adenoma bearing patients, while consistently increase in the blood of CRC patients, even if from stage II only.
References
[1]
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127: 2893–2917.
[2]
Quirke P, Risio M, Lambert R, von Karsa L, Vieth M (2011) Quality assurance in pathology in colorectal cancer screening and diagnosis - European recommendations. Virchows Arch 458: 1–19.
[3]
Tenesa A, Dunlop MG (2009) New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10: 353–358.
[4]
Lanza G, Messerini L, Gafà R, Risio M (2011) Colorectal tumors: the histology report. Dig Liver Dis 43: 344–355.
[5]
Gala M, Chung DC (2011) Hereditary colon cancer syndromes. Semin Oncol 38: 490–499.
[6]
Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22: 231–237.
[7]
Oshima H, Oshima M (2012) The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. J Gastroenterol 47: 97–106.
[8]
Ning Y, Lenz HJ (2012) Targeting IL-8 in colorectal cancer. Expert Opin Ther Targets 13: 491–497.
[9]
Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, et al. (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133: 1019–1031.
[10]
Blobe GC, Schiemann WB, Lodish HF (2000) Role of transforming growth factor-beta in human disease. N Engl J Med 342: 1350–1358.
[11]
Teicher BA (2001) Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev 20: 133–143.
Biasi F, Mascia C, Poli G (2008) The contribution of animal fat oxidation products to colon carcinogenesis, through modulation of TGF-beta1 signaling. Carcinogenesis 29: 890–894.
[14]
Bellam N, Pasche B (2010) Tgf-beta signaling alterations and colon cancer. Cancer Treat Res 155: 85–103.
[15]
Biasi F, Tessitore L, Zanetti D, Cutrin JC, Zingaro B, et al. (2002) Associated changes of lipid peroxidation and transforming growth factor beta1 levels in human colon cancer during tumour progression. Gut 50: 361–367.
[16]
Xu Y, Pasche B (2007) TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet 16: 14–20.
[17]
Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 17: 347–362.
[18]
De Gramont A, de Gramont A, Chibaudel B, Bachet JB, Larsen AK, et al. (2011) From chemotherapy to targeted therapy in adjuvant treatment for stage III colon cancer. Semin Oncol 38: 521–532.
[19]
Hasan MR, Ho SH, Owen DA, Tai IT (2011) Inhibition of VEGF induces cellular senescence in colorectal cancer cells. Int J Cancer 129: 2115–2123.
[20]
Mysliwiec AG, Ornstein DL (2002) Matrix metalloproteinases in colorectal cancer. Clin Colorectal Cancer 1: 208–219.
[21]
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549–555.
[22]
Becker C, Fantini MC, Wirtz S, Nikolaev A, Lehr HA, et al. (2005) IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 4: 217–220.
[23]
Csiszár A, Szentes T, Haraszti B, Balázs A, Petrányi, et al (2004) The pattern of cytokine gene expression in human colorectal carcinoma. Pathol Oncol Res 10: 109–116.
[24]
Chung YC, Chang YF (2003) Significance of inflammatory cytokines in the progression of colorectal cancer. Hepatogastroenterology 50: 1910–1913.
[25]
Kamińska J, Kowalska MM, Nowacki MP, Chwaliński MG, Rysińska A, et al. (2000) CRP, TNF-alpha, IL-1ra, IL-6, IL-8 and IL-10 in blood serum of colorectal cancer patients. Pathol Oncol Res 6: 38–41.
[26]
Rubie C, Frick VO, Pfeil S, Wagner M, Kollmar O, et al. (2007) Correlation of IL-8 with induction, progression and metastatic potential of colorectal cancer. World J Gastroenterol 13: 4996–5002.
[27]
Dimberg J, Str？m K, L？fgren S, Zar N, Lindh M, et al. (2011) DNA promoter methylation status and protein expression of interleukin-8 in human colorectal adenocarcinomas. Int J Colorectal Dis. Available: http://www.springerlink.com/content/b0w4？305647006335/Accessed 2011 Nov 24.
[28]
Kemik O, Kemik A, Begenik H, Erdur F, Emre H, et al. (2012) The relationship among acute-phase responce proteins, cytokines, and hormones in various gastrointestinal cancer types patients with cachectic. Hum Exp Toxicol 31: 117–125.
[29]
Bünger S, Haug U, Kelly FM, Klempt-Giessing K, Cartwright A, et al. (2011) Toward standardized high-throughput serum diagnostics: multiplex-protein array identifies IL-8 and VEGF as serum markers for colon cancer. J Biomol Screen 16: 1018–1026.
[30]
Miyazaki T, Okada N, Ishibashi K, Ogata K, Ohsawa,T, et al (2008) Clinical significance of plasma level of vascular endothelial growth factor-C in patients with colorectal cancer. Jpn J Clin Oncol 38: 839–43.
[31]
Khromova N, Kopnin P, Rybko V, Kopnin BP (2012) Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene 31: 1389–1397.
[32]
Li X, Liu B, Xiao J, Yuan Y, Ma J, et al. (2011) Roles of VEGF-C and Smad4 in the lymphangiogenesis, lymphatic metastasis, and prognosis in colon cancer. J Gastrointest Surg 15: 2001–2010.
[33]
Lampropoulos P, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas,N, et al (2011) TGF-beta signalling in colon carcinogenesis. Cancer Lett 314: 1–7.
[34]
Hurst NG, Stocken DD, Wilson S, Keh C, Wakelam MJ, et al. (2007) Elevated serum matrix metalloproteinase 9 (MMP-9) concentration predicts the presence of colorectal neoplasia in symptomatic patients. Br J Cancer 97: 971–977.
[35]
Chu D, Zhao Z, Zhou Y, Li Y, Li J, et al. (2012) Matrix metalloproteinase-9 is associated with relapse and prognosis of patients with colorectal cancer. Ann Surg Oncol 19: 318–325.
