The Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment

Abstract

Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.

The Contribution of Chemoattractant GPCRs, Formylpeptide Receptors, to Inflammation and Cancer

“…FPRs expressed by leukocytes and tumor cells are subjected to regulation by a variety of PAMPs and cytokines that control cell function in complex microenvironment milieu (32)(33)(34). This provides the opportunity to better understand the mechanistic basis of many diseases as well as to benefit the design of therapeutic strategies at different molecular levels.…”

“…The increased expression of Fpr2 by microglial cells also promotes endocytosis and degradation of Aβ42 by the cells, a consequence thought to be beneficial for the host. However, long term exposure of microglial cells to high concentration of Aβ42 causes accumulation of the amyloid peptide in the cells to form the core for plaques, resulting in breakdown of the cells and inflammatory responses detrimental to neuronal cells (34). The ability of proinflammatory stimulants to enhance the expression of functional Fpr2 in microglial cells was attenuated by anti-inflammatory cytokines such as IL-4 (85) and TGFβ1 (86) through interference of the activation of key intracellular pathways such as MAPKs and NFκB.…”

“…However, whether the inhibitory effect of antiinflammatory cytokines on Fpr2 induction by pro-inflammatory stimulants is beneficial remains unclear. Nevertheless, a logical view is that the fine-tuning of Fpr2 function in microglial cells should be important for amplifying host clearance of abnormally aggregated Aβ42 peptides and in the meantime, reducing neuronal damage caused by overt inflammatory responses [Figure 2; (34)].…”

“…The diverse functions of FPRs (Fprs) are attributable to their interaction with a plethora of pathogen-associated and damage-associated chemotactic molecular patterns (PAMPs and DAMPs) (23,(31)(32)(33)(34). However, due to the mounting evidence for the important functions of FPRs (Fprs) in patho-physiological conditions, this review would only cover relatively narrow aspects of these receptors, i.e., their role in inflammatory responses and cancer progression.…”

Piracy on the molecular level: human herpesviruses manipulate cellular chemotaxis

“…This process is essential for appropriate tissue maintenance, homeostasis, formation, repair and pathogen clearance (Turner et al, 2014;Zhou et al, 2014). Dysregulation of the delicate balance of cellular signals and/or improper positioning could impede these processes.…”