Inflammation and cancer

Abstract

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Figure 1

Wound healing versus invasive tumour growth. a, Normal tissues have a highly organized and segregated architecture. Epithelial cells sit atop a basement membrane separated from the vascularized stromal (dermis) compartment. Upon wounding or tissue assault, platelets are activated and form a haemostatic plug where they release vasoactive mediators that regulate vascular permeability, influx of serum fibrinogen, and formation of the fibrin clot. Chemotactic factors such as transforming growth factor-β and platelet-derived growth factor, derived from activated platelets, initiate granulation tissue formation, activation of fibroblasts, and induction and activation of proteolytic enzymes necessary for remodelling of the extracellular matrix (for example, matrix metalloproteinases and urokinase-type plasminogen activator). In combination, granulocytes, monocytes and fibroblasts are recruited, the venous network restored, and re-epithelialization across the wound occurs. Epithelial and stromal cell types engage in a reciprocal signalling dialogue to facilitate healing. Once the wound is healed, the reciprocal signalling subsides. b, Invasive carcinomas are less organized. Neoplasia-associated angiogenesis and lymphangiogenesis produces a chaotic vascular organization of blood vessels and lymphatics where neoplastic cells interact with other cell types (mesenchymal, haematopoietic and lymphoid) and a remodelled extracellular matrix. Although the vascular network is not disrupted in the same way during neoplastic progression as it is during wounding, many reciprocal interactions occur in parallel. Neoplastic cells produce an array of cytokines and chemokines that are mitogenic and/or chemoattractants for granulocytes, mast cells, monocytes/macrophages, fibroblasts and endothelial cells. In addition, activated fibroblasts and infiltrating inflammatory cells secrete proteolytic enzymes, cytokines and chemokines, which are mitogenic for neoplastic cells, as well as endothelial cells involved in neoangiogenesis and lymphangiogenesis. These factors potentiate tumour growth, stimulate angiogenesis, induce fibroblast migration and maturation, and enable metastatic spread via engagement with either the venous or lymphatic networks.

Figure 2

Cytokine and chemokine balances regulate neoplastic outcome. The balance of cytokines in any given tumour is critical for regulating the type and extent of inflammatory infiltrate that forms. Tumours that produce little or no cytokines or an overabundance of anti-inflammatory cytokines induce limited inflammatory and vascular responses, resulting in constrained tumour growth. In contrast, production of an abundance of pro-inflammatory cytokines can lead to a level of inflammation that potentiates angiogenesis, thus favouring neoplastic growth. Alternatively, high levels of monocytes and/or neutrophil infiltration, in response to an altered balance of pro-versus anti-inflammatory cytokines, can be associated with cytotoxicity, angiostasis and tumour regression. In tumours, interleukin-10 is generally a product of tumour cells and tumour-associated macrophages.

Figure 3

Cancer metastasis and chemokine signalling. Initiated epithelial cells are promoted by inflammation to undergo neoplastic progression, a process that requires remodelling of the extracellular matrix, recruitment of inflammatory cells, angiogenesis and lymphangiogenesis. Out of this microenvironment, carcinomas arise. These neoplastic cells then turn on expression of chemokine receptors, such as CXCR4. The production of chemokine ligands for these receptors, in sites such as lymph nodes, bone marrow, liver and lung, then facilitates their invasion and migration to secondary sites where malignant cells reside either in a dormant state, or proliferate to form a productive metastatic lesion. Blockade of chemokine receptors, for example, anti-CXCR4 antibodies, attenuates metastatic spread in some experimental systems.