Dipartimento di Oncologia - test

Descrizione del progetto

Responsabile Scientifico: Prof Mario Nano

Colorectal carcinoma (CRC) is one of the most common malignant tumors worldwide, with one million new cases diagnosed each year. Almost 60% of cases occur in developed countries, and in Europe it is the second cause of cancer-related death CRC may develop from adenomatous polyps (adenomas), the precursor lesions, whose malignant potential depends on their size, morphology, and grade of dysplasia The fact that this type of malignant tumor commonly arises from adenomatous polyps has been proven in the case of hereditary colon cancer syndromes, which may carry up to 100% risk of carcinoma, as in familial adenomatous polyposis In the last few years, the role of inflammation in the initiation and progression of colorectal carcinoma has been investigated in greater depth. Inflammatory reactions are associated with almost all types of malignant tumors, and are known to promote tumor proliferation, angiogenesis and metastasis, and to increase resistance to hormonal or chemo-therapies. Monocyte/macrophage cells are usually the major component of the inflammatory infiltrate in the microenvironment of most malignant tumors; they are thus called tumor-associated macrophages (TAM). Phagocyte infiltration begins early in the non-invasive stage of the tumor, and continues progressively with an evident but gradual switch from the M1 pro-inflammatory phenotype to the M2 cancer-promoting phenotype. This event directly influences behavior and function of tumor cells, and promotes tissue remodeling and repair, immunomodulation, angiogenesis, and tumor progression  Notably, colorectal cancer cells, stimulated by preexisting inflammation, or driven by intrinsic pathways related to gene defects, may also secrete different cytokines, and activate the local stromal cells to do likewise Among the cytokines involved in inflammation-associated intestinal tumorigenesis, an important role is played by interleukin-6 (IL-6) and interleukin-8 (IL-8). Both have been found over-expressed in CRC with increased angiogenic and metastatic potential The IL-6 and IL-8-dependent inflammatory network appears to significantly contribute to relating oncogene-induced cellular senescence with an inflammatory phenotype and tumor progression Other inflammation-related molecules, such as transforming growth factor b1 (TGFb1), vascular endothelial growth factor (VEGF) and matrix metalloproteases (MMPs), become predominant during advanced tumor stages TGFb1 is an important cytokine, which probably plays a major role in the association of inflammation and carcinogenesis. Under physiological conditions, this pleiotropic peptide is involved in regulating cell processes including proliferation, survival, differentiation and apoptosis: TGFb1 inhibits the growth of epithelial cells, including intestinal epithelial cells, by enhancing differentiation and apoptotic pathways, while it promotes the proliferation of fibroblasts and myofibroblasts, as well as the deposition of extracellular matrix Further, TGFb1 is an extremely potent immunosuppressive factor that inhibits proliferation, activation and differentiation of immune effector cells, thus its over-expression might contribute to promoting the invasive and metastatic behavior of tumor cells [. Indeed, in a previous study on a series of colorectal cancers, at different stages, from I to IV, the amount of TGFb1 was found significantly increased only in the most advanced cancer stage Derangement of the TGFb1 signal transduction pathway, mediated by mutations or polymorphisms of its receptors and/or of the transduction molecules, SMADs, is considered to play a primary role in the development and progression of several types of cancer in humans In addition, the derangement of TGFb1 receptors, TGFb1RI or TGFb1RII, can contribute to colon cancer formation and metastasis. Our previous experience with a series of 15 patients, who had undergone CRC surgical resection, led to the observation of a significant reduction of TGFb1RI (7/15) and TGFb1RII (3/15) in the tumor mass versus the apparently normal surrounding colonic mucosa [12]. Further, mutations in the TGFb1RII are estimated to occur in approximately 30% of CRC On the basis of the current literature, sufficient data are now available concerning TGFb1RI and TGFb1RII changes in established CRC, but the trend of these molecules during the early phases of carcinogenesis, i.e. in benign tumors of the colorectum, remains to be defined.

VEGF has emerged as a critical mediator of angiogenesis, required for invasive tumor growth and metastasis and, therefore, targeted antibodies against VEGF and its receptors have been introduced as potential antitumor therapy Inflammatory cytokines themselves are potent activators of MMPs, enzymes that demolish extracellular matrix proteins and that are likely involved in all steps of colorectal carcinogenesis. However, notwithstanding their likely involvement in this process, the available data do not elucidate the actual trend of their serum levels during both benign and malignant phases of colorectal carcinogenesis The same applies to the levels of here investigated cytokines, which are considered as macrophage markers of phenotypes 1 and 2 by Mantovani and co-workers In this paper, a comprehensive group of patients affected by either benign (adenomas) or malignant (adenocarcinomas) colorectal tumors at different stages was investigated. The goals  of our recherchs are: i) to define the trend of serum levels of IL-8, IL-6, TGFb1, VEGF and MMPs, throughout the entire manifest process of colorectal carcinogenesis; ii) to compare the trend of the inflammatory cytokines IL-8 and IL-6 with that of C-reactive protein (CRP); iii) to characterize fully the behavior of TGFb1RI and TGFb1RII in tissue specimens from colorectal adenomas and different stages of adenocarcinomas.