Cellular and molecular pathways linking inflammation and cancer

Abstract

Several experimental and epidemiological evidence indicate that, irrespective of the trigger for the development (chronic infection/inflammation or genetic alteration), a “smouldering” inflammation is associated with the most of, if not all, tumours and supports their progression.

Several evidence have highlighted that tumours promote a constant influx of myelomonocytic cells that express inflammatory mediators supporting pro-tumoral functions. Myelomonocytic cells are key orchestrators of cancer-related inflammation associated with proliferation and survival of malignant cells, subversion of adaptive immune response, angiogenesis, stroma remodelling and metastasis formation.

Although the connection between inflammation and cancer is unequivocal the mechanistic basis of such association are largely unknown. Recent advances in the understanding of the cellular and molecular pathways involved in cancer-related inflammation as well as their potential relevance as diagnostic, prognostic and therapeutic targets are herein discussed.

Introduction

Although the progress achieved by new diagnostic and therapeutic treatments has led to a declined mortality rate, cancers remain one of the major cause of death in industrialized countries. The progressive sequence of mutations and epigenetic alterations of cancer-related genes promote the malignant transformation of cancer progenitor cells by disrupting key processes that are involved in the control of normal cell growth and tissue homeostasis. In addiction to genetic alterations, inflammatory cells and circuits characterize the tumour microenvironment and represent crucial players in the tumour development and progression (Balkwill et al. 2005; Balkwill and Mantovani 2001; Coussens and Werb 2002; Karin 2006).

The inflammation–cancer link can be view as consisting of two pathways: an extrinsic pathway driven by inflammatory signals (e.g. infections) and autoimmune diseases (e.g. inflammatory bowel disease) and an intrinsic pathway driven by genetic alterations that cause both inflammation and neoplasia (Mantovani et al. 2008). Thus, irrespective of the trigger for the development, the presence of inflammatory cells and mediators in tumour tissues, tissue remodelling and angiogenesis similar to that seen in chronic inflammatory responses and tissue repair are hallmarks of most of, if not all tumours. Several studies have highlighted that a leukocytes infiltrate, varying in size, composition and distribution is present in the majority of tumours and is involved in carcinogenesis, tumour growth, invasion and metastasis (Coussens et al. 2000; Lin et al. 2001; Mantovani et al. 1992). In particular tumour growth is paralleled by recruitment and accumulation of myelomonocytic cells; macrophages in particular (Sica and Bronte 2007).

Altough these cells have the ability to prevent the establishment and the spread of tumour cells, several evidence indicate that, in established cancers, these cells acquire functions supporting tumour growth and dissemination (Mantovani et al., 2004, Mantovani et al., 2002; Sica et al. 2006). Their phenotypic switch during tumour development may depend on the functional plasticity characterizing these cells. Indeed, in response to different microenvironmental signals macrophages can express different “polarized” functional programs (Mantovani et al. 2005). However, up to date, the tumour-derived signals promoting the skewing of myeloid cell functions are poorly known.

In this review we discuss current knowledge about the cellular and molecular basis promoting cancer-related inflammation. The elucidation of these mechanisms may offer the opportunity to develop strategies and drugs that could act in synergism with conventional therapeutics and further overcome the problems due to the high grade of genetic instability of characterized malignant cells.