World J Gastroenterol 2015 October 7; 21(37): 10493-10501 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

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TOPIC HIGHLIGHT 2015 Advances in Gastric Cancer

Targeting mast cells in gastric cancer with special reference to bone metastases Christian Leporini, Michele Ammendola, Ilaria Marech, Giuseppe Sammarco, Rosario Sacco, Cosmo Damiano Gadaleta, Caroline Oakley, Emilio Russo, Giovambattista De Sarro, Girolamo Ranieri Christian Leporini, Emilio Russo, Giovambattista De Sarro, Department of Health Science, Clinical Pharmacology and Pharmacovigilance Unit and Pharmacovigilance’s Centre Calabria Region, University of Catanzaro “Magna Graecia” Medical School, Viale Europa - Germaneto, 88100 Catanzaro, Italy Michele Ammendola, Giuseppe Sammarco, Rosario Sacco, Department of Medical and Surgery Sciences, Clinical Surgery Unit, University of Catanzaro “Magna Graecia” Medical School, 88100 Catanzaro, Italy Ilaria Marech, Cosmo Damiano Gadaleta, Caroline Oakley, Girolamo Ranieri, Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, “Giovanni Paolo II”, 70124 Bari, Italy Author contributions: Leporini C, Ammendola M, Marech I and Ranieri G conceived the review and performed the critical review of the literature; Sammarco G, Sacco R, Gadaleta CD, Russo E and De Sarro G contributed to the literature research and data analysis; all authors wrote the manuscript and Oakley c edited the manuscript. Conflict-of-interest statement: The authors declare no conflicts of interest. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Correspondence to: Michele Ammendola, MD, Department of Medical and Surgery Sciences, Clinical Surgery Unit, University of Catanzaro “Magna Graecia” Medical School, Viale Europa Germaneto, 88100 Catanzaro, Italy. [email protected]

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Telephone: +39-961-3694191 Fax: +39-961-3647556 Received: April 5, 2015 Peer-review started: April 7, 2015 First decision: April 23, 2015 Revised: June 15, 2015 Accepted: August 25, 2015 Article in press: August 25, 2015 Published online: October 7, 2015

Abstract Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumorinfiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients

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affected by bone metastases. Key words: Bone metastases; Gastric cancer; receptor activator of nuclear factor-kB; Angiogenesis; Osteoclastic bone resorption; Tryptase inhibitors; c-Kit receptor tyrosine kinase inhibitors; Anti-angiogenic therapy © The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: The activation of the stem cell factor/c-Kit receptor (c-KitR) pathway in mast cells (MCs), and tryptase release upon MCs degranulation have a pivotal role in tumor angiogenesis in several human malignancies. MCs positive to tryptase (MCPT) have been implicated in primary gastric cancer (GC) an­ giogenesis. Our preliminary findings indicated that bone metastasis angiogenesis from GC is also supported by infiltrating MCPTs. Overall, the evidence provides a rationale to evaluate c-KitR inhibitors that block MCs degranulation, or tryptase inhibitors that inhibit tryptase and/or the Proteinase-Activated Receptor-2 pathway, in clinical trials for bone metastasis GC patients. Leporini C, Ammendola M, Marech I, Sammarco G, Sacco R, Gadaleta CD, Oakley C, Russo E, De Sarro G, Ranieri G. Targeting mast cells in gastric cancer with special reference to bone metastases. World J Gastroenterol 2015; 21(37): 10493-10501 Available from: URL: http://www.wjgnet. com/1007-9327/full/v21/i37/10493.htm DOI: http://dx.doi. org/10.3748/wjg.v21.i37.10493

INTRODUCTION Gastric cancer (GC) is a major cause of cancer-related [1] mortality worldwide . According to GLOBOCAN estimates, there were 260000 cases of cardia GC and [1] 691000 cases of non-cardia GC in 2012 . Generally, at the time of diagnosis, most patients have unresectable [2] or metastatic disease . The most common site of distant metastases is the peritoneum, followed by [2,3] the liver, lung and bones . Bone metastases are a [4] relatively uncommon finding , occurring in between 1% and 20% of GCs. Notably, they represent a major discomfort because of the related pain, neurological [5,6] involvement and hypercalcemia syndrome . Recently, it was reported that bone metastases diagnosed by Fluorine-18- fluorodeoxyglucose positron emission tomography/computed tomography examinations [7] represented 10% of an evaluated series . In fact, many GC patients die from metastases in intraperitoneal organs before their bone metastatic sites are revealed. Both primary GC and its metastatic progression rely [8,9] on angiogenesis , which plays a crucial role in cancer development, inducing tumor growth, invasion and [10,11] metastasis . Moreover, cancer stem cells also promote GC metastasis via close physical cellular contact and paracrine signals released from the

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tumor niche, both in vivo and in vitro. In fact, stromaassociated cancer stem cells promote the GC cell epithelial to mesenchymal transition (EMT), attracting circulating cancer cells to self-seed the primary tumor, [12] again though EMT . Interestingly, a large body of evidence supports the substantial involvement of mast cells (MCs) [9,13-17] in tumor angiogenesis . A preclinical pivotal study documented that the angiogenic response to subcutaneously growing B16-BL6 tumors was lower in genetically MC-deficient W/Wv mice compared +/+ with MC-sufficient littermate mice. Moreover, the latters showed a greater propensity to develop lung [18] metastases . Accordingly, a significant increase in MCs density (MCD) was observed in several animal [19-22] and human malignant tumors . MCs secrete several classical and non-classical pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor-β (PDGF-β), interleukin-6 (IL-6), IL-8, thymidine phosphorylase [23-27] (TP), chymase and tryptase . Notably, tryptase is the most powerful non-classical pro-angiogenic factor released by MCs upon c-Kit [28] receptor (c-KitR) TK activation . Tryptase induced [29] endothelial cell (EC) proliferation in a matrigel assay and in vivo in a chick embryo chorioallantoic membrane [27] (CAM) assay : tryptase inhibitors suppressed both effects consistently. Tryptase activates the proteinaseactivated receptor-2 (PAR-2) expressed on ECs, directly [17,30] stimulating their proliferation . Interestingly, PAR-2 expression is greater in tumor tissues than in normal [31] tissues . Moreover, it also promotes the degradation of extracellular matrix (ECM) components via metal­ loproteinases activation, resulting in the release of ECMbound latent pro-angiogenic factors (e.g., VEGF and [32,33] FGF-2) . Most notably, many human studies have established a positive correlation between MCD positive to tryptase (MCDPT) and microvascular density (MVD) [9,13,14,34-39] in tumor tissue . Several findings from patients strongly support the crucial involvement of MCDPT in primary gastric [28,39-41] tumor angiogenesis . There is also a significant correlation between MCDPT and angiogenesis in bone [42] metastases from GC patients . Starting from these preliminary results, we aim to review: (1) the involvement of MCDPT in GC angio­ genesis; (2) the specific role that MCDPT might play in bone metastases angiogenesis; and (3) the potential targeting of MCDPT by tryptase or c-KitR tyrosine kinase (TK) inhibitors in metastatic gastric patients with special reference to bone metastases.

MCDPT AND TUMOR ANGIOGENESIS MCs are cells that originate in the bone marrow + [43] from pluripotent CD34 hematopoietic stem cells . Precursors of MCs migrate through the circulation to their target tissues, completing their maturation

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Leporini C et al . Mast cells in advanced gastric cancer process into granulated cells, under the influence of [44] several microenvironment growth factors . The most important of the above factors is the ligand for the c-KitR TK, stem cell factor (SCF), secreted mainly by fibroblasts and ECs. SCF also regulates development, [33,45] survival and de novo proliferation of MCs . MCs express the high affinity IgE receptor, which, following IgE activation, triggers release of their stored proangiogenic factors. In this way a link between immunity and angiogenesis is established by MCs. Among the other IgE-independent MCs activation mechanisms, a wide variety of other surface receptors for cytokines, chemokines, immunoglobulins, complement and [46] bacterial products, are also described . MCs granules are key functional elements, cha­ racterized by two distinct secretory patterns: exocytosis [33] or piecemeal degranulation . Interestingly, this latter mechanism, representing a slow and selective pathway of cell secretion, has been more frequently observed in MCs infiltrating areas of chronic inflammation, such [47] as tumor tissues . Correspondingly, a link between MCs, chronic inflammation and cancer has been long [23,47] suggested . Thus, MCs are one of the earliest and major inflammatory cell types recruited into the tumor [9,13,14,39,48] microenvironment . In particular, several data from human studies have highlighted a strong linear correlation between MCDPT and pathological angiogenesis sustaining several solid tumors, such as human malignant melanoma, endometrial carcinoma, breast cancer, GC, colorectal cancer (CRC) [9,14,20,21,28,34-39,49-51] and pancreatic ductal adenocarcinoma . Remarkably, MCDPT correlated with angiogenesis, tumor aggressiveness and poor tumor outcome in most [9,16,23,33] clinical investigations , suggesting a prognostic [14,21,35,39,50-52] significance for MCDPT in several tumors . [28] Moreover, Ammendola et al demonstrated a positive correlation among MCDPT, c-KitR expressing cells and MVD in tumor tissue specimens from surgical GC patients, confirming that c-KitR activation on MCs surface, resulting in tryptase degranulation from activated [24,53] MCs, has a pivotal function in tumor angiogenesis . Thus, MCDPT may represent a novel and attra­ ctive therapeutic target of anti-angiogenic cancer [33,45] therapy . Indeed, MCDPT-targeted therapeutic approaches could limit angiogenesis in growing tumors, potentially decreasing tumor growth and metastasis. Therefore, tryptase inhibitors, such as gabexate [54] mesylate and nafamostat mesylate , or c-KitR [10,55,56] inhibitors, such as imatinib and masitinib , should be evaluated in clinical trials as new anti-angiogenic agents in combination with chemotherapy.

MCDPT, ANGIOGENESIS, AND IMMUNE SUPPRESSION IN HUMAN CANCERS: THE DUAL VALUE OF TARGETING MCDPT Different infiltrating cell populations form the tumor

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microenvironment, enabling a pathological condition that directly promotes angiogenesis, tumor spread and [57] invasion and, concurrently, hamper the immune [58] response against tumors . However, a relationship between high MCD and improved overall survival has [59] also been reported in some human studies , signifying a diversified and not yet well-understood role for MCs in cancer. Note that, with reference to this relationship between high MCD and favorable prognosis, MCs are able to modulate both innate and adaptive immune [60] responses . In this context, MCs are involved in innate immunity by releasing tumor necrosis factor-α (TNF-α) and interleukins (IL-1, 4, 6) that, in turn, help to kill [24,46] tumors . In addition, MCs express both the major histocompatibility class (MCH) Ⅱ antigen and its costimulatory molecule, which activate adaptive T and B [61] cell responses against tumors . Finally, MCs cooperate [61] with natural killer cells to reject cancer cells . On [62] the other hand, Shin et al reported the critical involvement of MCs’ tryptase in eosinophils recruitment, suggesting a role in the induction of a pro-inflammatory microenvironment. In this way, MCDPT may also induce angiogenesis via several pro-inflammatory cytokines [23,33] that act as pro-angiogenic factors . Taken together, the data confirm the potential dual value of MCPT as a therapeutic target for tryptase inhibitors or c-KitR tyrosine kinase inhibitors, which could both prevent MCDPT-mediated immune suppression and promote/ unleash protective anti-tumor immune responses through the selective inhibition of MCDPT-mediated angiogenesis, resulting in tumor regression.

MCDPT AND ANGIOGENESIS IN HUMAN GC Several studies support the view that inflammation is a critical component of GC development and [24,53,63] progression . In turn, increasing evidence sug­ gests an intimate relationship between angiogenesis, [16] inflammation and GC progression . In the GC microen­ vironment, many types of inflammatory cells exist, and among them, MCs promote GC angiogenesis by secreting pro-angiogenic factors and cooperating with stromal and malignant cells. In turn, neovascularization helps to maintain inflammation by promoting the migration of [16,63,64] inflammatory cells to the site of inflammation . From a translational point of view, a significant positive correlation between MCDPT and MVD has been confirmed in cancer tissue specimens. Interestingly, specimens from patients with advanced histological stages of the disease showed a higher MCD than those [65,66] from patients with early stage disease . [9] Similarly, Ribatti et al observed that stage IV GC shows a higher degree of vascularization than the earlier stages, and that MCDPT increases in parallel with malignancy grade and is highly correlated with the extent of angiogenesis in primary tumor tissue. [67] Zhao et al reported a significant positive correlation

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Leporini C et al . Mast cells in advanced gastric cancer Table 1 Principal studies that correlate mast cell density and mast cells density positive status to tryptase with angiogenesis or negative prognostic factors in gastric cancer patients Disease stage/ main stages

Chemotherapy

Patients (n )/site

Methods of MCs identification

Correlation

P value

Ribatti et al[9], 2010

All TNM stages (mainly Ⅱ-Ⅳ)

No

30

All TNM stages (mainly Ⅱ-Ⅳ) TNM stage Ⅲ TNM stage Ⅲ

No

60

Nr

25

Nr

19

MCD and Angiogenesis and advanced tumor stage MCD and advanced tumor stage MCDPT and MVD and c-KitR-EC MCDPT and no. of metastatic lymph nodes

< 0.05

Zhao et al[67], 2012

Immunohistochemistry primary anti-tryptase and anti-chymase Abs Immunohistochemistry primary anti-tryptase Ab Immunohistochemistry primary anti-tryptase Ab Immunohistochemistry primary anti-tryptase Ab

Ref.

Ammendola et al[28], 2013 Ammendola et al[32], 2013

NS 0.001 0.01

Ab/s: Antibody/antibodies; MCD: Mast cell density; NR: Not reported; MCDPT: Mast cells density positive to tryptase; c-KitR EC: c-Kit receptor expressing cell.

between the increased infiltration of MCDPT and the progression of disease in GC patients, documenting an association between a high level of tryptase expression and advanced tumor stage, which is a marker of poor prognosis. In agreement with the above findings, a more recent investigation evaluating biopsy specimens from 25 GC patients highlighted a positive correlation between MCDPT, c-KitR expressing cells and MVD, using [28] immunohistochemistry and image analysis methods . Furthermore, in a series of 41 gastrointestinal cancer patients, a positive correlation between MCDPT and the number of metastatic lymph nodes harvested, and between MCDPT in primary tumor tissue and [39] in metastatic lymph node tissue, were observed . These results suggested that MCs’ tryptase, like VEGF, could be involved in tumor lymphangiogenesis, which, in turn, is correlated with lymph node metastases, both in experimental cancer models and several [68] human cancers . Table 1 summarizes the above studies correlating MCD with angiogenesis or negative prognostic factors. Overall, the majority of studies in GC support the view that MCDPT is significantly correlated with the depth of invasion, lymph node metastases, lymphatic or blood invasion, the degree of histological differentiation, and the number of blood vessels surrounding GC cells. Most of the MCs located near the neovascularization areas were degranulated, suggesting the critical role of tryptase in angiogenesis [8] and tumor progression . Correspondingly, tumors injected into mice treated with inhibitors of MCsdegranulation presented decreased vascularization, [65,69] growth and metastasis . Data from an ultra-structural study in advanced GC patients highlighted that perivascular MCs containing only tryptase in their granules exhibited piecemeal degranulation that was significantly associated with microvascular basal lamina changes (irregular thickness, multiple layers and loose association with ECs and pericytes), which fitted with a remodeling of existing microvasculature. These changes are involved in the increased vascular permeability that characterizes

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[70]

the tumor microvasculature . Interestingly, this suggested that MCs’ tryptase, through its direct and indirect proteolytic activity on the ECM, could induce fenestrations in the endothelium of tumor [71] microvasculature, like VEGF ; thus, specifically contributing to metastasis in GC. In light of these evidence-based considerations, serum tryptase released by MCs could be an indicator for future surgery, a valid predictive factor for hematogenous invasion or metastasis, and a promising prognosis marker both in early and advanced GC. Taken together, the evidence suggests that the accumulation of MCDPT at the periphery of GC tissue might lead to increased rates of tumor vascularization, thus promoting tumor growth and metastases to distant organs. Therefore, MCDPT may represent a valuable target of anti-angiogenic therapy, either by tryptase inhibitors or c-KitR inhibitors, which may prove useful therapeutic tools to control angiogenesismediated tumor growth, progression and metastasis in GC.

ROLE OF MCDPT IN BONE METASTASIS ANGIOGENESIS FROM PRIMARY GC Bone metastases from GC arise from a scattered metastatic spread of tumor cells in the bone marrow (most frequently located in the thoracic and lumbar [72] vertebrae) . These metastases are mainly osteolytic, [5,6,73-75] while osteoblastic implants are rarely reported . Notably, bone metastases in GC usually occur in the advanced stages of the disease, generally correlating [2,5,6,73,74] with poor prognosis . However, the dissemination of micrometastatic cells in the bone tissue may be evident in early GC, in which a poorly-differentiated carcinoma, the presence of signet-ring cell carcinoma, and/or the involvement of lymph node metastasis, seem [76] to be risk factors associated with bone metastases . In particular, in bone marrow micrometastases in early GC, subclinical seeding of tumor cells in the bone marrow (at the time of primary tumor resection) was detected by

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Leporini C et al . Mast cells in advanced gastric cancer immunocytochemical evaluation of epithelial cytokeratin protein, a distinctive trait of epithelial cells, both normal and malignant, that would not normally be present [77] in the hematogenous marrow . According to Jauch [78] et al , cytokeratin-positive cells in the bone marrow represent a surrogate marker for general disseminative metastasis, rather than the beginning of metastatic growth in patients with GC. Interestingly, patients with cytokeratin positivity in their bone marrow had a higher [40,77] MVD compared with cytokeratin-negative patients . Correspondingly, VEGF-positive tumors associated with increased MVD show cytokeratin-positive cells in [8] the bone marrow . As a result, the above reported occurrence of such micrometastases (cytokeratinpositive cells) in the bone marrow is potentially closely [8,40] related to angiogenesis in the primary tumor . These observations suggested that angiogenesis plays an essential role in micrometastatic (subclinical) seeding of GC cells in the bone tissue, in the develop­ ment of bone marrow micrometastases into clinically manifest bone metastases (macroscopic disease) and in their potential to invade circulatory system for further distant dissemination from the bone microenvironment. Recently, we investigated infiltrating MCDPT and neovascularization in 15 bone tissue metastases selected from a series of 190 GC patients. We evaluated bone biopsies samples from these patients using immunohistochemistry and image analysis methods. The results showed a statistically significant correlation among MCDPT, MC-area-PT, MVD and endothelial [42] area . These correlations suggested the involvement of infiltrating MCDPT in bone metastasis angiogenesis from primary GC, as well as in primary tumor neovascularization. Therefore, an MCDPT-stimulated angiogenic process could support the development of metastases in the bone tissue. From a biological point of view, MCs may be both recruited and activated by [58,79] SCF , the ligand for c-KitR, and by other growth factors, such as VEGF, FGF-2 and TP, secreted by [8,27,29,80,81] metastasized bone marrow GC cells . Proangiogenic factors, released from activated MCs, may act in autocrine and paracrine manners, and [51,82] then stimulate MCs, ECs and GC cells, as [51] reported by Marech et al . Interestingly, the bone tumor microenvironment plays a crucial role in os­ teoclastogenesis by inducing the production of the receptor activator of nuclear factor-kB (RANK) ligand (RANKL) by marrow stromal cells and osteoblasts. Tumor cells secrete parathyroid hormone-related peptide (PTH-rP) and several other osteotropic factors, including IL-6, TNF, M-CSF and prostaglandin E2 (PGE2), which upregulate the expression of RANKL on the surface of marrow stromal cells and immature osteoblasts. RANKL then binds RANK on the surface of osteoclast precursors, ultimately resulting in osteoclast formation and bone resorption. Thus, tumor-induced osteoclastic bone resorption leads to the release of growth factors, such as TGF-β, FGFs, PDGFs, insulin-

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like growth factors, and bone morphogenetic proteins by the bone matrix that promote tumor growth and further bone destruction by increasing the production of PTH-rP, as well as the above growth factors, resulting in [83] further RANKL upregulation . This reciprocal interplay between tumor cells and the bone tumor microenvironment results in a vicious circle that further increases tumor growth and bone [83] destruction . Crucially, MCDPT could foster this “symbiotic relationship” between bone destruction and tumor growth by releasing pivotal components of the [84,85] above-described vicious circle . The involvement of MCDPT both in metastatic bone resorption and in angiogenesis-mediated GC cell growth is also suggested by MCs ability to produce and [23] release TGF-β , which stimulates osteoclast activation [54,86] via the RANKL pathway . Furthermore, TGF-β, in the presence of M-CSF and in the absence of RANKL, could induce in vitro [87] osteoclast formation directly , suggesting that MCDPT, by releasing TGF-β, could also stimulate the RANKL-independent metastatic bone resorption in [81,88] the bone tissue metastases from GC patients . Based on the discussed data, MCDPT may potentially offer a novel and promising target of anti-angiogenic therapy to decrease both angiogenesis-mediated GC cell growth in the bone tissue and tumor-induced [2,8,42] osteoclastic bone resorption .

TARGETING MCDPT: A POSSIBLE ANTIANGIOGENIC AND ANTI-RESORPTIVE STRATEGY IN BONE METASTASIS GC PATIENTS The use of MCs’ tryptase inhibitors (gabexate mesylate, [17] nafamostat mesylate and tranilast) or c-KitR tyrosine [10,28,55] kinase inhibitors (imatinib and masitinib) could represent a potential anti-tumor strategy to inhibit both angiogenesis and RANKL-/non-RANKL-mediated [42] osteoclast activation . Unlike conventional chemotherapy, anti-angiogenic therapy does not induce a direct cytotoxic effect, but reduces neovascularization mainly by targeting small foci of proliferating cells of tumor-associated capillary endothelium or from metastatic sites. Thus, angiogenesis inhibitors generally do not cause suppression of the hematogenous bone marrow, hair loss or gastrointestinal symptoms like cytotoxic chemotherapeutics, which require pause periods to allow regeneration of normal cells. By virtue of these features, angiogenesis inhibitors need to be administered for a longer period compared with conventional cytotoxic chemotherapeutics and, consequently, anti-angiogenic [89] therapy is administered continuously . Therefore, anti-angiogenic agents may be effective for longterm administration to achieve prolonged dormancy of [40] primary GC and GC micrometastases .

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Leporini C et al . Mast cells in advanced gastric cancer Furthermore, the characteristics of anti-angiogenic therapy have recently prompted the medical-scientific community to consider using anti-angiogenic agents in combination with traditional cytotoxic anti-cancer drugs to potentiate the clinical effectiveness of the latter by preventing their limitations. Moreover, MCs’ tryptase or c-KitR inhibitors could be added to avail­ able conventional cytotoxic drugs that target normal marrow and GC cells indiscriminately in the bone tissue from bone metastasis GC patients. In particular, these anti-angiogenic agents might temporarily inhibit the remodeling of tumor microvasculature and, consequently, the increase of tumor microvascular permeability in the bone metastases from primary GC patients. Starting from the consideration that tumorassociated vasculature represents the first barrier to the penetration of drugs into tumors, agents such as gabexate mesylate and nafamostat mesylate, or imatinib and masitinib, could act as anti-angiogenic modulators by impairing tumor vasculature functions in the bone tumor microenvironment, possibly resulting in the potentiation of the therapeutic response when administered in combination with cytotoxic chemo­ therapy, and potentially prolonging the survival time of GC patients with bone metastases. Notably, synergism between MCs’ tryptase inhibitors and classical chemotherapy drugs in cancer treatment is exemplified by the ability of nafamostat mesylate to inhibit both in vitro and in vivo chemotherapy[90,91] induced nuclear factor kappa-B (NF-kB) activation , which is well-known to contribute to the angiogenic [92] phenotype of several tumors , and chemoresistance and suboptimal therapeutic efficacy of cancer chemothe­ [93] rapy drugs . Correspondingly, it is interesting that nafamostat mesylate has been shown to enhance the anti-tumor effect of paclitaxel against GC with peritoneal dissemination by inhibiting paclitaxel-induced [94] NF-kB activation in mice . Thus, we speculate that a combination chemotherapy of nafamostat mesylate and classical cytotoxic drugs could potentially exert a synergistic anti-tumor effect in bone metastases from GC. Finally, MCDPT targeting agents, such as tryptase inhibitors or c-KitR receptor inhibitors, could represent a novel potential anti-angiogenic approach to inhibit tumor-induced osteoclastic bone resorption and bone destruction in bone metastasis GC patients. Intriguingly, the potential ability of MCDPT targeting to inhibit the RANKL-dependent vicious circle of cancer-induced bone destruction, supports further investigation of tryptase inhibitors or c-KitR inhibitors [95] in clinical trials comparing them with denosumab (a well-known inhibitor of the RANKL–RANK interaction), in terms of efficacy and safety, in the prevention of skeletal-related events in adult patients with bone metastases from GC. Importantly, unlike denosumab, MCDPT-targeting agents could decrease angiogenesismediated GC cell growth in the bone tissue and metastatic bone resorption, independently of their

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inhibitory activity on the cycle of bone destruction and tumor growth mediated by RANKL. Therefore, it would be interesting to investigate whether combination therapy with these agents, which are potentially antiangiogenic and anti-resorptive, and denosumab may exert a clinically useful, synergistic effect in decrea­ sing tumor-induced osteoclastic bone resorption and angiogenesis-mediated bone metastasis progression in primary GC patients affected by bone metastases. Accordingly, clinical studies comparing the efficacy and safety profile of MCDPT targeting agents versus other [96] anti-resorptive drugs, such as bisphosphonates , in bone metastasis GC patients might be also worth performing.

CONCLUSION A survey of the literature data indicated that MCs are important players in tumor angiogenesis and [15,33,61] development , by releasing a panoply of angiogenic [23] factors (e.g., tryptase) . This is supported by human studies that highlighted a strong correlation between MCDPT and pathological angiogenesis in various solid [9,14,20,21,28,34-39,49-51] tumors . With special reference to GC, much evidence supports the involvement of MCDPT in primary gastric tumor [8,9,28,39-41] angiogenesis, thus promoting metastases . With regards to the subgroup of bone metastases, pilot published data demonstrated a significant correlation [42] between infiltrating MCDPT and angiogenesis . From a therapeutic point of view, tumors injected in mice treated with inhibitors of MCs-degranulation [65,69] presented decreased vascularization and metastasis . According to these data, targeting MCs is currently under [56,97] investigation, especially in GC patients . In particular, for the subgroup of patients with bone metastases from GC, the biological background suggests that MCDPT may stimulate the RANKL-dependent vicious circle of tumor-induced bone destruction and tumor growth, and the RANKL-independent metastatic bone resorption. This biological background further supports targeting of MCDPT as a therapeutic strategy in bone metastases. Finally, ad hoc clinical trials might be performed to compare, in terms of efficacy and safety, these potential anti-angiogenic and anti-resorptive agents with anti-resorptive drugs currently used clinically (i.e., denosumab and bisphosphonates) for the prevention of skeletal-related events in GC patients affected by bone metastases.

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L, Dammacco F. Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. Eur J Cancer 2003; 39: 666-674 [PMID: 12628847] Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Invest 2003; 33: 420-425 [PMID: 12760367] Ribatti D, Finato N, Crivellato E, Marzullo A, Mangieri D, Nico B, Vacca A, Beltrami CA. Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer. Am J Obstet Gynecol 2005; 193: 1961-1965 [PMID: 16325597 DOI: 10.1016/j.ajog.2005.04.055] Ribatti D, Finato N, Crivellato E, Guidolin D, Longo V, Mangieri D, Nico B, Vacca A, Beltrami CA. Angiogenesis and mast cells in human breast cancer sentinel lymph nodes with and without micrometastases. Histopathology 2007; 51: 837-842 [PMID: 17944928 DOI: 10.1111/j.1365-2559.2007.02869.x] Ribatti D, Belloni AS, Nico B, Salà G, Longo V, Mangieri D, Crivellato E, Nussdorfer GG. Tryptase- and leptin-positive mast cells correlate with vascular density in uterine leiomyomas. Am J Obstet Gynecol 2007; 196: 470.e1-470.e7 [PMID: 17466707 DOI: 10.1016/ j.ajog.2006.12.039] Ammendola M, Sacco R, Donato G, Zuccalà V, Russo E, Luposella M, Vescio G, Rizzuto A, Patruno R, De Sarro G, Montemurro S, Sammarco G, Ranieri G. Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology 2013; 85: 111-116 [PMID: 23887206 DOI: 10.1159/000351145] Kakeji Y, Maehara Y, Sumiyoshi Y, Oda S, Emi Y. Angiogenesis as a target for gastric cancer. Surgery 2002; 131: S48-S54 [PMID: 11821787] Kakeji Y, Koga T, Sumiyoshi Y, Shibahara K, Oda S, Maehara Y, Sugimachi K. Clinical significance of vascular endothelial growth factor expression in gastric cancer. J Exp Clin Cancer Res 2002; 21: 125-129 [PMID: 12071518] Ammendola M, Marech I, Sammarco G, Zuccalà V, Luposella M, Zizzo N, Patruno R, Crovace A, Ruggieri E, Zito AF, Gadaleta CD, Sacco R, Ranieri G. Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients. Int J Mol Sci 2015; 16: 3237-3250 [PMID: 25648323 DOI: 10.3390/ ijms16023237] Gurish MF, Boyce JA. Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 2006; 117: 1285-1291 [PMID: 16750988 DOI: 10.1016/ j.jaci.2006.04.017] Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA 2005; 102: 11408-11413 [PMID: 16006518 DOI: 10.1073/ pnas.0504197102] Iemura A, Tsai M, Ando A, Wershil BK, Galli SJ. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am J Pathol 1994; 144: 321-328 [PMID: 7508684] Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol 2004; 4: 787-799 [PMID: 15459670 DOI: 10.1038/nri1460] Crivellato E, Ribatti D. The mast cell: an evolutionary perspective. Biol Rev Camb Philos Soc 2010; 85: 347-360 [PMID: 19961471 DOI: 10.1111/j.1469-185X.2009.00105.x] Mangia A, Malfettone A, Rossi R, Paradiso A, Ranieri G, Simone G, Resta L. Tissue remodelling in breast cancer: human mast cell tryptase as an initiator of myofibroblast differentiation. Histopathology 2011; 58: 1096-1106 [PMID: 21707711 DOI: 10.1111/j.1365-2559.2011.03842.x] Benítez-Bribiesca L, Wong A, Utrera D, Castellanos E. The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem 2001; 49: 1061-1062 [PMID: 11457936] Acikalin MF, Oner U, Topçu I, Yaşar B, Kiper H, Colak E. Tumour angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas. Dig Liver Dis 2005; 37: 162-169 [PMID:

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