Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

Pittoni, Paola; Piconese, Silvia; Tripodo, Claudio; Colombo, Mario P.

doi:10.1038/onc.2010.494

Cited by 67 publications

(52 citation statements)

References 130 publications

(141 reference statements)

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“…Taken together, these data suggest that Kit W-sh/W-sh mice developed exacerbated EAE independently from T-cell priming, peripheral MC presence or granulocytic effector cell alterations. Beside MCs, other cells of the immune system may express c-Kit at variable levels and under different circumstances, 44 such as dendritic cells (DCs). 45 C-Kit pharmacological inhibition fosters a productive cross-talk between DCs and natural killer (NK) cells 46 and promotes the differentiation of a DC subset endowed with cytotoxic ability and IFN-g competence.…”

Section: Alterations In the Granulocytementioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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Mast cell (MC)-deficient c-Kit mutant Kit W/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit W-sh/W-sh . Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced chronic EAE was exacerbated in Kit W-sh/W-sh compared with Kit þ / þ mice. Kit W-sh/W-sh mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit W-sh/W-sh and in Kit W/W-v mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG and adjuvants. Although Kit W-sh/W-sh mice exhibited exacerbated EAE under all immunization protocols, Kit W/W-v mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit W-sh/W-sh mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit W-sh/W-sh mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. MCs are key factors in IgE-associated immediate hypersensitivity reactions, during which they release a wide spectrum of inflammatory mediators in response to IgE and antigen (Ag) stimulation. 1 However, recent findings have pointed out that MCs may exert also important effector and/or immunomodulatory functions in other physiopathological conditions as venom detoxification, pathogen clearance, tumor growth, contact hypersensitivity, allograft acceptance and autoimmunity. 2 Most of these studies have assessed the in vivo role of MCs by the use of mouse models carrying spontaneous mutations in c-Kit receptor (WBB6F 1 -Kit W/W-v or C57BL/6-Kit W-sh/W-sh mice) or c-Kit ligand (WCB6F 1 -Kitl Sl /Kitl Sl-d ), which show severe deficiency of MC populations. 3,4 MCs may either enhance or suppress the inflammation associated to different types of autoimmune diseases. MC-deficient Kit W/W-v and Kitl Sl/Sl-d mice are protected from autoantibodymediated models of rheumatoid arthritis and bullous pemphigoid, inflammatory disorders affecting, respectively, the joint and the skin. Reconstitution of Kit W/W-v mice with bone marrow derived, in vitro cultured MCs (BMMCs) restores complete disease susceptibility in both conditions, thus indicating a proinflammatory role of these cells in such diseases. 5,6 Conversely, MCs seem to exert a protective function in experimental autoimmune glomerulonephritis, by limiting clinical and histological glomerular pathology and mortality. 7,8 However, recent work has shown that, unlike Kit W/W-v , Ki...

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Section: Alterations In the Granulocytementioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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“…7 However, recent insights into the roles of CD117 in cancer shed important light on the different types of CD117-expressing tumors. Broadly, CD117-expressing tumors can be classified into two main groups: 25 (1) those characterized by gain-offunction (activating) CD117 mutations and derived from cells that normally express CD117. In these cases, CD117 has a central pathogenetic role in neoplasm initiation; (2) those with rare occurrence of CD117 mutations, in which tumors are composed of cells that normally do not express CD117.…”

Section: Discussionmentioning

confidence: 99%

CD117 expression in breast phyllodes tumors correlates with adverse pathologic parameters and reduced survival

et al. 2015

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and 5 Duke-NUS Graduate Medical School, Singapore CD117 (c-kit) is a type III receptor tyrosine kinase encoded by the KIT gene. Deregulation of expression and mutations in the gene are implicated in various tumors. Reports of CD117 expression in phyllodes tumors have been controversial. We aim to investigate the protein expression of CD117 and mutations in the KIT gene in phyllodes tumors, and correlate the findings with pathological parameters and clinical outcome. A total of 272 cases were included in this study. CD117 expression was investigated by immunohistochemistry on tissue microarray sections. Toluidine blue staining was performed to indicate mast cells. Overall, 28 (10%) cases were CD117 positive. CD117 expression was significantly associated with tumor grade (Po0.001), increased stromal hypercellularity (P ¼ 0.003), stromal atypia (P ¼ 0.01), and stromal mitotic activity (Po0.001), permeative microscopic margins (P ¼ 0.002), and presence of hemorrhage (P ¼ 0.001). Expression was also associated with poorer overall survival (P ¼ 0.003). Nineteen cases were further selected for mutation screening through the Affymetrix OncoScan platform. No mutation of the KIT gene was found. Despite a lack of mutations in the KIT gene, CD117 protein expression is associated with unfavorable pathological parameters and poorer prognosis, suggesting an underlying role in the biology of phyllodes tumors.

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“…Thus, targeting the recruitment of mast cells to the tumor microenvironment may help suppress growth of the tumor vasculature and enhance recognition of tumors by the immune system. Targeting the SCF/ KIT axis, or downstream mediators like FES, within the tumor microenvironment may have benefits for patients with KIT-negative mammary tumors (8). However, a recent study in a prostate cancer model suggests that targeting mast cells may alter not just tumor growth but also the tumor phenotype (12,19).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in immunocompromised mouse models have shown that the immune system protects against outgrowth of both spontaneous and carcinogen-induced primary tumors (3)(4)(5)(6). In contrast, recruitment of innate immune cells such as macrophages and mast cells to the tumor microenvironment has been linked to creating an inflammatory state driving tumor progression (7)(8)(9). Increased density of tumor-associated macrophages (TAM) has been linked to increased tumor vasculature and metastasis in multiple cancer types (10).…”

Section: Introductionmentioning

confidence: 99%

“…Mast cells also accumulate at the periphery of tumors and release a variety of mediators that regulate tumor angiogenesis, immunosuppression, and tumor growth (11). Depending on tumor type, stage, and tissue microenvironment, mast cells can either enhance or suppress tumor growth (8). Interestingly, one recent study shows that mast cell targeting can reduce onset of prostate adenocarcinoma, but also leads to development of more highly malignant neuroendocrine tumors in these mice (12).…”

Section: Introductionmentioning

confidence: 99%

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FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

Kwok

Everingham

Zhang

et al. 2012

Molecular Cancer Research

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KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow-derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerizationdisrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosinebinding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT-and FESdependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement. Mol Cancer Res; 10(7); 881-91. Ó2012 AACR.

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Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

Cited by 67 publications

References 130 publications

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

CD117 expression in breast phyllodes tumors correlates with adverse pathologic parameters and reduced survival

FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis

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