Chemokines and chemokine receptors: new insights into cancer-related inflammation

Chemokines are involved in cellular interactions and tropism in situations frequently associated with inflammation. Recently, the importance of chemokines and chemokine receptors in inflammation associated with carcinogenesis has been highlighted. Increasing evidence suggests that chemokines are produced by tumor cells as well as by cells of the tumor microenvironment including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, tumor-associated macrophages (TAMs) and more recently tumor-associated neutrophils (TANs). In addition to affecting tumor cell proliferation, angiogenesis and metastasis, chemokines also seem to modulate senescence and cell survival. Here, we review recent progress on the roles of chemokines and chemokine receptors in cancer-related inflammation, and discuss the mechanisms underlying chemokine action in cancer that might facilitate the development of novel therapies in the future.

Introduction

Chemokines are chemotactic cytokines (approximately 8-17 kDa) with the ability to bind G-protein-coupled receptors (Box 1). Chemokines were originally identified as potent attractants for leukocytes such as neutrophils and monocytes, and were generally regarded as mediators of acute and chronic inflammation (inflammatory chemokines). Several chemokines were subsequently found to be constitutively expressed in lymphoid tissues. Moreover, leukocytes also express specific chemokines and their receptors. Accumulating evidence suggests that in addition to inflammation, chemokines are important regulators in development, homeostasis and pathophysiological processes associated with osteoporosis [1], obesity and insulin resistance [2], viral infections 3, 4, immune responses 5, 6, mobilization of progenitors to the bone marrow [7] and autoimmune encephalomyelitis [8].

More recently, chemokines and their receptors have been identified as mediators of chronic inflammation, which plays a key role in the initiation or progression of cancers of the lung, colon, liver, breast, cervix, prostate, bladder, ovary, esophagus, skin and lymphatics 9, 10, 11, 12. Tumor growth and dissemination is the result of dynamic interactions between tumor cells themselves, and also with components of the tumor environment. In this regard, chemokines are emerging as key mediators not only in the homing of cancer cells to metastatic sites but also in the recruitment of a number of different cell types to the tumor microenvironment.

Several studies have suggested that cancer cells express chemokine receptors that mediate metastasis to target organs expressing their cognate chemokines. Furthermore, recent studies have suggested that chemokines are produced by epithelial cancer cells, leading to the recruitment of TAMs, TANs, lymphocytes, CAFs, MSCs and endothelial cells into the tumor microenvironment. These infiltrating cells provide a secondary source of chemokines that could affect tumor growth, cell survival, senescence, angiogenesis and metastasis. Here, we review the role of chemokines and chemokine receptors in cancer-related inflammation. These novel findings provide a rationale for developing therapies that target chemokines as well as their receptors.