Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by a dysregulated inflammatory response.

Friday, 07/05/2010  |   Chemokines  |  no comments

Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by a dysregulated inflammatory response. The identification of transcription factors such as NF-kB, AP-1 and STAT3 and their gene products such as tumour necrosis factor, interleukin-1, interleukin-6, chemokines, cyclooxygenase-2, 5 lipooxygenase, matrix metalloproteases, and vascular endothelial growth factor, adhesion molecules and others have provided the molecular basis for the role of inflammation in cancer (Aggarwal & Gehlot 2009). The following articles review the impact of chemokines on tumour progression and metastases. In a future post, I will look at those herbs and compounds that are seen to down-regulate chemokines and reduce angiogenesis. Send me your email address, so you won’t miss it.

The tumour microenvironment is extremely complex that depends on tumour cell interaction with the responding host cells. Angiogenesis, or new blood vessel growth from pre-existing vasculature, is a preeminent feature of successful tumour growth of all solid tumours. While a number of factors produced by both the tumour cells and host responding cells have been discovered that regulate angiogenesis, increasing evidence is growing to support the important role of CXC chemokines in this process. As a family of cytokines, the CXC chemokines are pleiotropic in their ability to regulate tumour-associated angiogenesis, as well as cancer cell metastases. In this chapter, we will discuss the disparate activity that CXC chemokines play in regulating cancer-associated angiogenesis and metastases (Keeley et al 2005).

Chemokines play a paramount role in the tumour progression. Chronic inflammation promotes tumour formation. Both tumour cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumour cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumour angiogenesis and leukocyte infiltration into the tumour microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumour cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma-associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12–CXCR4 axis facilitates metastasis to distant organs and the CCL21–CCR7 chemokine ligand–receptor pair favours metastasis to lymph nodes. These two chemokine ligand–receptor systems are common key mediators of tumour cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumour progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumour are reviewed (Raman et al 2007).

The inflammatory response is a highly co-ordinated process involving multiple factors acting in a complex network as stimulators or inhibitors. Upon infection, the sequential release of exogenous agents (e.g. bacterial and viral products) and induction of endogenous mediators (e.g. cytokines and chemokines) contribute to the recruitment of circulating leukocytes to the inflamed tissue. Microbial products trigger multiple cell types to release cytokines, which in turn are potent inducers of chemokines. Primary cytokines act as endogenous activators of the immune response, whereas inducible chemokines act as secondary mediators to attract leukocytes. Interaction between exogenous and endogenous mediators thus enhances the inflammatory response. In this review, the synergistic interaction between cytokines to induce chemokine production and the molecular mechanisms of the cooperation amongst co-induced chemokines to further increase leukocyte recruitment to the site of inflammation are discussed (Gouwy et al 2005).

Aggarwal, B.B. & Gehlot, P. Inflammation and cancer: how friendly is the relationship for cancer patients? Current Opinion in Pharmacology 2009, 9:Pp. 351–69. DOI 10.1016/j.coph.2009.06.020

Gouwy, M., Struyf, S., Proost, P. & Van Damme, J. Role of chemokines in tumour growth. Cytokine & Growth Factor Reviews. Vol 16, Issue 6, December 2005, Pp. 561-80. doi:10.1016/j.cytogfr.2005.03.005

Keeley, E.C., Mehrad, B. & Strieter, R.M. CXC Chemokines in Cancer Angiogenesis and Metastases. Current Topics in Membranes. Vol 55, 2005, Pp. 255-88. doi:10.1016/S1063-5823(04)55010-X

Raman, D., Baugher, P.J., Thu, Y.M. & Richmond, A. Cancer Letters. Vol 256, Issue 2, 28 October 2007, Pp. 137-65. doi:10.1016/j.canlet.2007.05.013

Chemokines, or chemotactic cytokines, and their receptors have been discovered as essential and selective mediators in leukocyte migration to inflammatory sites and to secondary lymphoid organs. Besides their functions in the immune system, they also play a critical role in tumour initiation, promotion and progression. There are four subgroups of chemokines: CXC, CC, CX3C, and C chemokine ligands. The CXC or ? subgroup is further subdivided in the ELR+ and ELR? chemokines.
Members that contain the ELR motif bind to CXC chemokine receptor 2 (CXCR2) and are angiogenic. In contrast, most of the CXC chemokines without ELR motif bind to CXCR3 and are angiostatic. An exception is the angiogenic ELR?CXC chemokine stromal cell-derived factor-1 (CXCL12/SDF-1), which binds to CXCR4 and CXCR7 and is implicated in tumor metastasis. This review is focusing on the role of CXC chemokines and their receptors in tumourigenesis, including angiogenesis, attraction of leukocytes to tumour sites and induction of tumour cell migration and homing in metastatic sites (Vandercappellen et al 2008).

Vandercappellen, J., Van Damme, J. & Struy, S. The role of CXC chemokines and their receptors in cancer. Cancer Letters. Vol 267, Issue 2, 28 August 2008, Pp. 226-44. doi:10.1016/j.canlet.2008.04.050

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