Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

Abstract

Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.

Cyclic Hypoxia Induces Transcriptomic Changes in Mast Cells Leading to a Hyperresponsive Phenotype after FcεRI Cross-Linking

“…Possible explanations for this phenomenon include the potential influence of specific TMEs on MC phenotype, which could lead MCs to synthesize particular mediators able to favor or limit tumor cell replication, blood vessel formation, or intratumoral immune response. To date, the mediators and conditions modulating MC activation in particular TMEs have not been fully described, and potential phenotypic changes on tumor-associated MCs (TAMCs) are largely unknown [ 13 , 21 , 22 ], although TAMCs seem to constitute a particular subpopulation of MCs that are different to the classical categories that have been used to date [ 59 ]. From all the factors present in the TME that activate MCs and can modify their phenotype (such as stem cell factor, adenosine, and IL-33, among others), cyH is one of the least studied.…”

“…In addition, a recent study demonstrated that MCs exposed to chH (24 h at 1% O 2 ) increased the secretion of the chemokine CCL-2, and this secretion was dependent on ROS formation and the translocation of L-type Ca 2+ channels to the plasma membrane [ 28 ]. Interestingly, hypoxic MCs also promoted the translocation of lysosome-associated membrane protein 2 (LAMP2)-positive vesicles from intracellular pools to the plasma membrane [ 13 ]. LAMP translocation has been associated with the activation of MCs and basophils [ 79 ], since it can be related to the mobilization of granules to the plasma membrane and, eventually, to an increase in MCs degranulation [ 80 ].…”

“…Evidence indicates a close relationship between MCs and tumors in both human and animal cancer models [ 13 , 14 ]. Indeed, there is overwhelming evidence that MCs can infiltrate different types of solid tumors, including melanoma [ 13 , 15 , 16 ].…”

“…Evidence indicates a close relationship between MCs and tumors in both human and animal cancer models [ 13 , 14 ]. Indeed, there is overwhelming evidence that MCs can infiltrate different types of solid tumors, including melanoma [ 13 , 15 , 16 ]. Once there, they are known as tumor-associated MCs (TAMCs) and might play a critical role in promoting and/or limiting tumorigenesis [ 17 , 18 ].…”

“…Given that MCs possess high phenotypic plasticity, it has been proposed that TAMCs could differentiate into at least two phenotypes within the tumor: MC1 (antitumoral) and MC2 (protumoral), and this phenotypic change could occur in response to stimuli from the TME [ 13 , 21 , 22 ]. TME is characterized by hypoxia, an intrinsic feature of all solid tumors [ 23 ].…”