Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Mobilization of Macrophage Lineage Cells from Bone Marrow and Stimulates Solid Tumor Growth

Matsushima, Masashi; Yamamoto, Seiji; Osawa, Tsuyoshi; Shibuya, Masabumi

doi:10.1158/0008-5472.can-10-0202

Cited by 86 publications

(69 citation statements)

References 45 publications

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“…Preclinical tumor xenografts have been used to define many of the mechanisms with the potential to influence response to VEGFi, other angiogenic factors (7), bone marrow-derived cells (5,6), or by recruitment of stromal fibroblasts/pericytes into the tumor which drive the maturation of tumor vessels (8)(9)(10). Our analysis suggests that those mechanisms of resistance defined in preclinical tumor xenografts may be most relevant to those diseases that display a tumor vessel phenotype.…”

Section: Discussionmentioning

confidence: 94%

“…Additional studies in preclinical models have revealed a number of putative mechanisms that may contribute to both intrinsic and acquired VEGFi resistance. One of the first mechanisms proposed as mediating resistance to VEGF-A neutralization was the presence or recruitment of inflammatory infiltrate, specifically CD11b, GR-1-positive cells derived from the bone marrow, in response to upregulation of tumor-derived factors (5,6). A complementary resistance mechanism is the expression of factors that drive alternative angiogenic pathways such as high expression of the potent angiogenic stimulus FGF-2 (7).…”

Section: Introductionmentioning

confidence: 99%

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Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy

Smith

Baker

Farren

et al. 2013

Clinical Cancer Research

127

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Purpose: The aim of the study was to investigate the vascular and stromal architecture of preclinical tumor models and patient tumor specimens from malignancies with known clinical outcomes to VEGFi treatment, to gain insight into potential determinants of intrinsic sensitivity and resistance.Experimental Design: The tumor stroma architecture of preclinical and clinical tumor samples were analyzed by staining for CD31 and a-smooth muscle actin (a-SMA). Tumor models representative of each phenotype were then tested for sensitivity to the VEGFR2-blocking antibody DC101.Results: Human tumor types with high response rates to VEGF inhibitors (e.g., renal cell carcinoma) have vessels distributed amongst the tumor cells (a "tumor vessel" phenotype, TV). In contrast, those malignancies where single-agent responses are lower, such as non-small cell lung cancer (NSCLC), display a complex morphology involving the encapsulation of tumor cells within stroma that also supports the majority of vessels (a "stromal vessel" phenotype). Only 1 of 31 tumor xenograft models displayed the stromal vessel phenotype. Tumor vessel models were sensitive to VEGFR2-blocking antibody DC101, whereas the stromal vessel models were exclusively refractory. The tumor vessel phenotype was also associated with a better Response Evaluation Criteria in Solid Tumors (RECIST) response to bevacizumab þ chemotherapy in metastatic colorectal cancer (CRC).Conclusion: The tumor stromal architecture can differentiate between human tumor types that respond to a VEGF signaling inhibitor as single-agent therapy. In addition to reconciling the clinical experience with these agents versus their broad activity in preclinical models, these findings may help to select solid tumor types with intrinsic sensitivity to a VEGFi or other vascular-directed therapies.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy

Smith

Baker

Farren

et al. 2013

Clinical Cancer Research

127

View full text Add to dashboard Cite

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“…To complicate matters further, divergent tumor growth phenotypes have been reported when implanting tumors in a tyrosine kinase-dead FLT1 mutant mouse model, with some studies reporting a reduction in tumor growth/metastasis (Hiratsuka et al 2001(Hiratsuka et al , 2002Kerber et al 2008; Van de Veire et al 2010;Schmidt et al 2011) and others showing no effect (Dawson et al 2009;Bais et al 2010;Muramatsu et al 2010). Presumably, the importance of PlGF/ FLT1 is context-dependent.…”

Section: Plgf: a Multitasking Disease-restricted Cytokinementioning

confidence: 99%

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Dewerchin¹,

Carmeliet²

2012

Cold Spring Harbor Perspectives in Medicine

196

176

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“…A different population of VEGFR-1-expressing cells, circulating VEGFR-1-expressing hematopoietic cells, has recently been implicated in tumor growth and progression (12)(13)(14)(15). To exclude the possibility that we are in fact studying VEGFR-1-expressing hematopoietic cells, control experiments were done using pan-hematopoietic cell marker CD45.…”

Section: Chemotherapy Enhances Vegfr-1 Expression On Ecs In Vivomentioning

confidence: 99%

Chemotherapy Enhances Metastasis Formation via VEGFR-1–Expressing Endothelial Cells

et al. 2011

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Recent studies suggest that chemotherapy, in addition to its cytotoxic effects on tumor cells, can induce a cascade of host events to support tumor growth and spread. Here, we used an experimental pulmonary metastasis model to investigate the role of this host response in metastasis formation. Mice were pretreated with chemotherapy and after clearance of the drugs from circulation, tumor cells were administered intravenously to study potential "protumorigenic" host effects of chemotherapy. Pretreatment with the commonly used chemotherapeutic agents cisplatin and paclitaxel significantly enhanced lung metastasis in this model. This corresponded to enhanced adhesion of tumor cells to an endothelial cell monolayer that had been pretreated with chemotherapy in vitro. Interestingly, chemotherapy exposure enhanced the expression of VEGF receptor 1 (VEGFR-1) on endothelial cells both in vitro and in vivo. Administration of antibodies targeting VEGFR-1 reversed the early retention of tumor cells in the lungs, thereby preventing the formation of chemotherapy-induced pulmonary metastases. The data indicate that chemotherapy-induced expression of VEGFR-1 on endothelial cells can create an environment favorable to tumor cell homing. Inhibition of VEGFR-1 function may therefore be used to counteract chemotherapy-induced retention of tumor cells within the metastatic niche, providing a novel level of tumor control in chemotherapy. Cancer Res; 71(22); 6976-85. Ó2011 AACR.

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Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Mobilization of Macrophage Lineage Cells from Bone Marrow and Stimulates Solid Tumor Growth

Cited by 86 publications

References 45 publications

Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy

Tumor Stromal Architecture Can Define the Intrinsic Tumor Response to VEGF-Targeted Therapy

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

Chemotherapy Enhances Metastasis Formation via VEGFR-1–Expressing Endothelial Cells

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