Chronic inflammation: is it the driver or is it paving the road for malignant transformation?

Abstract

Chronic inflammation in well-defined mouse models such as Giα2 knock out mouse has been shown to trigger formation and expansion of hypoxic niches and also leads to up regulation of NFĸB, offering cells which have adapted their genetic machinery to hypoxia a unique survival advantage. These adapted cells have been shown to acquire stem cell-like capabilities as shown by up regulation of stem cell markers. Such long lived cells become permanent residents in sub mucosa and acquire a malignant phenotype from long-term exposure to noxious environmental agents due to a barrier defect secondary to down regulation of barrier proteins such as Zo1 and Occludin. Indeed mitotic spindle disorientation in such mice has been proposed as another contributory factor to malignant transformation. Sterilization of bowel lumen of these mice through different techniques has prevented malignant transformation in the presence of chronic inflammation. These facts stand strongly against chronic inflammation as a true driver of carcinogenesis but clearly support its role in facilitating the emergence of the neoplastic clone.

Keywords: Chronic inflammation; Free energy; JAK2V617F; bioenergetics; driver mutation; electric field and cancer; metabolomics; p53 Rb.

Figure 1. Suppressed expression of CCL2 (MCP-l) in the GBM cell line U251HF expressing transfected PAX6 (2.1, 2.2, and 2.3) as compared with non-transfected (p), vector transfected (vi, v6) and negative PAX6-transfected (2.6) cells

Cells were grownin DMEM/F12 under normoxic condition with serum deprivation for 24 and 48 hours before getting subjected to the assays. (A) Real-time qRT-PCR measurement of CCL2 expression normalized to ACTB and compared to the level in U25 1HF (p) with serum deprivation for 24 hours, using SYBR-Green I master mix (Roche) and Light Cycler real time PCR instruments following methods described previously 1. (B) ELISA quantification of secreted MCP-1 from the same cells analyzed in A, using MCP-1 ELISA kit from Assay Designs (Michigan). Values include the mean + SD of 3 independent experiments. PAX6 level in each cell line / transfectants by western blot assay was shown in ref. .