ReviewCancer-related inflammation: Common themes and therapeutic opportunities
Section snippets
Introduction to cancer-related inflammation
Smouldering, non-resolving inflammation is one of the consistent features of the tumor microenvironment. The connection between inflammation and cancer, first perceived in the nineteenth century is now accepted as enabling characteristic of cancer [1], [2]. Current estimates suggest that about 25% of cancers are associated with chronic inflammation sustained by infections (e.g. hepatitis) or inflammatory conditions of diverse origin (e.g. prostatitis) [1]. Moreover, tumors that are not
Polarization and diversity of inflammatory cells in the tumor microenvironment
Tumor associated macrophages (TAM) are a common component of CRI and will be used as a paradigm of its complexity. Cells of the monocyte–macrophage lineage exhibit considerable plasticity and diversity [1], [4], [5], [6], [7], [8]. TAM populations in murine tumors can be quite diverse and hypoxia may be one driver of this [9]. Subsets have been identified between mouse and human monocytes [8]. It remains to be determined whether diversity of TAM reflects their origin from different monocyte
Cytokines and cancer-related inflammation
TNF-α, IL-6 and IL-1 are among the most studied inflammatory cytokines in the tumor microenvironment and this review will focus on these.
Unlike their normal counterparts, many malignant cells constitutively produce small amounts of TNF-α. There is evidence from animal models that malignant cell-derived TNF-α enhances the growth and spread of syngeneic, xenogeneic, and carcinogen-induced tumors of skin, ovary, pancreas, pleural cavity and bowel (reviewed in Ref. [29]). For instance, in ovarian
Chemokines and cancer-related inflammation
Chemokines and their receptors are a key component of cancer-related inflammation affecting several pathways of tumor progression including leukocyte recruitment and function, cell senescence, tumor cell proliferation and survival, invasion and metastases [62].
CCL2 (MCP-1) and inflammatory CC chemokines have long associated to recruitment of TAM in tumors, in particular TAM [63], [64], [65]. Unequivocal genetic evidence for a non-redundant role of inflammatory CC chemokines in carcinogenesis
Therapeutic opportunities
Our understanding CRI has increased to the point when we can begin to translate our knowledge into new approaches to cancer prevention and treatment. This section will review some recent pre-clinical and clinical studies relating to the cells and soluble mediators of CRI.
Stimulating ‘good’ inflammation
Inflammation may not always be ‘bad’ in the context of malignant disease; the cancer cytokine network can also contribute to therapeutic response. It is a question of balance of individual members of the cytokine network. The actions of the cells and cytokines of inflammation in the tumor microenvironment are very context-dependent and one approach to cancer therapy is to attempt to switch the tumor-promoting immune suppressive microenvironment to one that kills tumor cells, is anti-angiogenic
Combining therapies
Over the past decade a number of exciting and more targeted cancer treatments have entered the clinic, a direct result of twenty-five years research into the genetic basis of malignant disease. Even these treatments, however, are liable to generate clones of cancer cells that overcome this specific receptor or signaling pathway blockade. Now that the importance of the inflammatory tumor microenvironment is recognized and early clinical trials are underway, the next steps are to devise and test
Prevention strategies
Everything we have learnt so far about cancer-related inflammation leads to the hypothesis that anti-inflammatory agents may have potential as cancer preventative agents. In terms of non-steroidal anti-inflammatory agents, there are several observational studies suggesting that aspirin reduces risk of certain cancers, e.g. [89]. A recent study of particular interest was an analysis of deaths due to cancer in a cohort of patients randomized to receive aspirin or placebo in trials originally
Biomarkers of CRI
Plasma or serum levels of inflammatory cytokines and chemokines, and in some cases their soluble receptors, are elevated in patients with a range of advanced cancers and this is generally a poor prognostic sign. For example, raised blood TNF-α levels generally associated with poor prognosis (reviewed in Ref. [99]). To take the example of prostate cancer, blood TNF-α concentrations are elevated in those patients with advanced, cachectic disease and TNF-α levels correlate positively with extent
Conflict of interest
None declared.
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