Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma and can lead to fibrotic evolution. In the colon mucosa, regulatory mechanisms, including TGF-β1, avoid damaging inflammation in front of the continuous challenge by the intestinal microbiome. Inducing either DSS colitis or AOM colorectal carcinogenesis in AVN-Wistar rats, we evaluated at one month after the end of each treatment whether immunological changes and remodelling of the collagen scaffold were already in development. At this time point, we found in both models a general downregulation of pro-inflammatory cytokines and even of TGF-β1, but not of IL-6. Moreover, we demonstrated by multi-photon microscopy the simultaneously presence of pro-fibrotic remodelling of the collagen scaffold, with measurable changes in comparison to the control mucosa. The scaffold was significantly modified depending on the type of induced stimulation. These results suggest that at one month after the end of the DSS or AOM inductions, a smouldering inflammation is present in both induced conditions, since the pro-inflammatory cytokines still exceed, in proportion, the local homeostatic regulation of which TGF-β1 is a part (inflammatory threshold). Such an inflammation appears sufficient to sustain remodelling of the collagen scaffold that may be taken as a possible pathological marker for revealing pre-neoplastic inflammation.

• Keywords
• AOM, DSS-induced colitis, IL-6, chronic inflammation, collagen, colorectal cancer, tissue scaffold, tumour niche,
• Publication type
• Journal Article MeSH

The lysyl oxidases (LOXs) are a family of enzymes deputed to cross-link collagen and elastin, shaping the structure and strength of the extracellular matrix (ECM). However, many novel "non-canonical" functions, alternative substrates, and regulatory mechanisms have been described and are being continuously elucidated. The activity of LOXs, therefore, appears to be integrated into a complex network of signals regulating many cell functions, including survival/proliferation/differentiation. Among these signaling pathways, TGF-β and PI3K/Akt/mTOR, in particular, cross-talk extensively with each other and with LOXs also initiating complex feedback loops which modulate the activity of LOXs and direct the remodeling of the ECM. A growing body of evidence indicates that LOXs are not only important in the homeostasis of the normal structure of the ECM, but are also implicated in the establishment and maturation of the tumor microenvironment. LOXs' association with advanced and metastatic cancer is well established; however, there is enough evidence to support a significant role of LOXs in the transformation of normal epithelial cells, in the accelerated tumor development and the induction of invasion of the premalignant epithelium. A better understanding of LOXs and their interactions with the different elements of the tumor immune microenvironment will prove invaluable in the design of novel anti-tumor strategies.

• Keywords
• CITIM 2019, Extracellular matrix structure, Immunity, Lysyl oxidases, TGF-β, Tumor microenvironment,
• MeSH
• Biomarkers MeSH
• Extracellular Matrix genetics   metabolism   MeSH
• Immunity * MeSH
• Humans MeSH
• Protein-Lysine 6-Oxidase chemistry   immunology   MeSH
• Multigene Family MeSH
• Tumor Microenvironment immunology   MeSH
• Neoplasms etiology   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers MeSH
• Protein-Lysine 6-Oxidase MeSH