Abstract
Tumor-related inflammation does influence the biological behavior of neoplastic cells and ultimately the patient’s outcome. With specific regard to thyroid cancer, the issue of tumor-associated inflammation has been extensively studied and recently reviewed. However, the role of chemokines, which play a crucial role in determining the immuno-phenotype of tumor-related inflammation, was not addressed in previous reviews on the topic. Experimental evidence shows that thyroid cancer cells actively secrete a wide spectrum of chemokines and, at least for some of them, solid scientific data support a role for these immune-active molecules in the aggressive behavior of the tumor. Our proposal for a review article on chemokines and thyroid cancer stems from the notion that chemokines, besides having the ability to attract and maintain immune cells at the tumor site, also produce several pro-tumorigenic actions, which include proangiogenetic, cytoproliferative, and pro-metastatic effects. Studies taking into account the role of CCL15, C–X–C motif ligand 12, CXCL16, CXCL1, CCL20, and CCL2 in the context of thyroid cancer will be reviewed with particular emphasis on CXCL8. The reason for focusing on CXCL8 is that this chemokine is the most studied one in human malignancies, displaying multifaceted pro-tumorigenic effects. These include enhancement of tumor cells growth, metastatization, and angiogenesis overall contributing to the progression of several cancers including thyroid cancer. We aim at reviewing current knowledge on the (i) ability of both normal and tumor thyroid cells to secrete CXCL8; (ii) direct/indirect pro-tumorigenic effects of CXCL8 demonstrated by in vitro and in vivo studies specifically performed on thyroid cancer cells; and (iii) pharmacologic strategies proven to be effective for lowering CXCL8 secretion and/or its effects on thyroid cancer cells.
Highlights
Reviewed by: Silvia Martina Ferrari, Università degli Studi di Pisa, Italy Salvatore Benvenga, Università degli Studi di Messina, Italy
Experimental evidence shows that thyroid cancer cells actively secrete a wide spectrum of chemokines and, at least for some of them, solid scientific data support a role for these immune-active molecules in the aggressive behavior of the tumor
Studies taking into account the role of CCL15, C–X–C motif ligand 12, CXCL16, CXCL1, CCL20, and CCL2 in the context of thyroid cancer will be reviewed with particular emphasis on CXCL8
Summary
Several studies in cancer patients showed that the inflammatory profile of tumor microenvironment is closely related to its biological behavior [8,9,10]. The tumor microenvironment is made of extracellular matrix and stromal cells, which include fibroblasts, vessel cells (endothelial cells, pericytes, and smooth muscle cells), and inflammatory leukocytes [lymphocytes, macrophages, dendritic cells (DCs), mast cells, and neutrophils] [13] These cells, either alone or in combination, potentially contribute to tumor growth, being their recruitment regulated by the presence of specific chemokines [13]. On the one hand, secreted chemokines by cancer-initiating cells and by normal surrounding cells may limit neoplastic progression by increasing leukocyte migration within the tumor, which eventually results in the induction of long-term antitumor immunity [15] Opposite to this process, other chemokines may facilitate tumor cell growth: (i) by recruiting endothelial cells; (ii) by subverting immunologic surveillance; and (iii) by maneuvering the tumor leukocyte profile, making feasible the escape from antitumor immune surveillance. Tumor cells actively secrete and, owing to the presence of specific receptors on their cell membrane, respond to chemokines, which represent essential mediators influencing tumor progression (Figure 1)
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