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

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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.

INTRODUCTION

The malignant transformation as per the free energy concept necessitates a significant and permanent decrease in the free energy of the malignant cell as a result of breakdown of the fine balance of cellular energetics[2]. Warburg effect offers a credible reflection of these deeply seated perturbances in cellular energetics and metabolism[4]. If chronic inflammation in well defined and valid mouse models would directly lead to break down of cellular energetics, then the assignment of a driver role to it would become meaningful. However evidence points to the contrary as discussed below. Indeed the cells that evolve in the inflammatory microenvironment under the effect of a myriad of cytokines and chemokines and adapt to the hypoxic niche, however fastidious continue to enjoy normal metabolism with no traces of Warburg effect in them[5].
There are many examples in which chronic inflammation is associated with carcinogenesis. However in none of them there is solid proof of a driver role for chronic inflammation[6, 7].....