Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

Sierra, J. Rafael; Corso, Simona; Caione, Luisa; Cepero, Virna; Conrotto, Paolo; Cignetti, Alessandro; Piacibello, Wanda; Kumanogoh, Atsushi; Kikutani, Hitoshi; Comoglio, Paolo M.; Tamagnone, Luca; Giordano, Silvia

doi:10.1084/jem.20072602

Cited by 235 publications

(210 citation statements)

References 49 publications

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“…Moreover, former data demonstrated soluble SEMA4D protein released from the breast cancer cell surface acted on local as well as distant tumor microenvironments, thus inducing tumor angiogenesis and metastasis (Basile et al, 2007). Furthermore, the same authors showed SEMA4D produced by TAMs not tumor cells per se enhanced tumor growth and angiogenesis in head and neck squamous cell carcinoma (HNSCC) (Sierra et al, 2008). The authors explained the seemingly contradictory results possibly due to differences between these tumor cell lines.…”

Section: Introductionmentioning

confidence: 97%

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Chen

Zhang²,

Lv³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related to tumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D in the EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advanced FIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations of SEMA4D expression and M2 macrophage counts in primary tumors and M2 macrophage percentage in ascites (r=0.281 and 0.355, each P<0.05). In the Cox proportional hazard mode, SEMA4D expression was an independent indicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higher expression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants were found than that in a human primary cultured ovarian cell and its supernatant by reversed transcript PCR (RT-PCR), Western blotting and ELISA, respectively. Interestingly, peripheral blood monocytes (MOs) tended towards the M2-polarized macrophage phenotype (CD163 high ) in vitro after human recombined soluble SEMA4D protein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis and could playan important role in promoting tumor dissemination and metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOC warrants further study.

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Section: Introductionmentioning

confidence: 97%

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Chen

Zhang²,

Lv³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…This scenario is now changed as some in vitro studies have made clear that M1 macrophages are only cytotoxic to tumor cells but not to normal cells and, therefore, these M1 cells help in the early eradication of neotrasfromed cells [48][49][50][51][52][53]. Another way by which M1 macrophages exert their antitumor activity is through their antagonistic action on tumor-promoting action of TAMs, myeloid-derived suppressor cells (MDSCs), M2 macrophages, regulatory macrophages, and immature myeloid cells (i.e., all these cells suppress adaptive tumor-specific immune response and promote tumor growth and development) [54][55][56][57][58][59]. The exact role of macrophages in early stages of cancer is still controversial and yet to be determined.…”

Section: Classically Activated Macrophages (M1 Macrophages)mentioning

confidence: 99%

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Kumar

2012

Purinergic Signalling

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Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

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“…The tyrosine phosphorylation of MET results in its activation and the recruitment of signaling effectors, such as the adaptor proteins Grb2 and Gab-1, which in turn promote the activation of diverse downstream signaling pathways, including the PI3K/AKT, Ras/RAF/MEK/ERK, PLC-g, FAK, and STAT3 pathways (4). Thereby, HGF-induced MET activation regulates a diverse set of biologic responses that include cell proliferation, survival, migration, invasion, angiogenesis, and branching morphogenesis (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

Du¹,

Caenepeel

Shen³

et al. 2016

Molecular Cancer Therapeutics

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Aberrant hepatocyte growth factor (HGF)/MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in hepatocellular carcinoma. We sought to investigate the in vitro and in vivo antitumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of hepatocellular carcinoma. The antiproliferative activity of AMG 337 was evaluated across a panel of hepatocellular carcinoma cell lines in a viability assay. Daily oral administration was used to evaluate the in vivo antitumor activity of AMG 337 in two patientderived xenograft (PDX) models of hepatocellular carcinoma (LI0612 and LI1078). AMG 337 exerted potent antiproliferative activity against 2 of 40 hepatocellular carcinoma cell lines, namely, MHCC97H (IC 50 , 0.015 mmol/L) and HCCLM3 (IC 50 , 0.025 mmol/L). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by FISH, and high MET expression (3þ IHC) assessed by IHC. AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, the dose-dependent inhibition of downstream effectors of HGF/MET signaling, including p-GAB1, p-AKT, and p-ERK, was limited to those cell lines sensitive to AMG 337 in a viability assay (MHCC97H and HCCLM3). AMG 337 significantly inhibited tumor growth at all doses tested in the MET-amplified and MET-high-expressing hepatocellular carcinoma PDX model LI0612 and had no effect on tumor growth in the non-METamplified and MET-low-expressing hepatocellular carcinoma PDX model LI1078. AMG 337 represents a promising and novel therapeutic strategy for targeting hepatocellular carcinomas with a dependence on HGF/MET signaling.

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Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

Cited by 235 publications

References 49 publications

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma

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