Altered tumor vessel maturation and proliferation in placenta growth factor‐producing tumors: Potential relationship to post‐therapy tumor angiogenesis and recurrence

Taylor, Alice P.; Rodriguez, M. C. Navarro; Adams, Kelly; Goldenberg, David M.; Blumenthal, Rosalyn D.

doi:10.1002/ijc.11059

Cited by 57 publications

(37 citation statements)

References 17 publications

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“…This novel finding for radiation recurrences may be consistent with a decrease in vessel maturation observed in tumor xenografts shortly before their apparent regrowth following radioimmunotherapy (17).…”

Section: Resultssupporting

confidence: 76%

Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti–Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors

et al. 2007

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The effects of antiangiogenic therapy on tumors relapsing after irradiation are not known. To this end, we irradiated human tumors growing s.c. in nude mice with a single dose of 20 or 30 Gy. Compared with primary (treatment-naive) xenografts, the growth rate of recurrent tumors was 1.6-fold slower, which is consistent with the known ''tumor bed effect.'' For similar size tumors, recurrences had fewer functional vessels, a reduced vessel coverage by perivascular cells, and were more necrotic. Placenta growth factor concentration was significantly lower in relapses, whereas vascular endothelial growth factor (VEGF) levels were similar between primary and recurrent tumors. On the other hand, fibrillar collagen deposition was significantly increased in recurrent tumors. This radiation-induced fibrosis was partially responsible for the slower growth of recurrences; the i.t. injection of collagenase increased the growth rate of tumor relapses without affecting primary tumor growth. The mouse-specific VEGF receptor 2-blocking antibody DC101 induced a 2.2-fold longer growth delay in recurrent tumors compared with treatment-naive tumors. DC101 significantly decreased the interstitial fluid pressure and did not change the functional vessel density and perivascular cell coverage in both tumor variants. Interestingly, DC101 induced a rapid (2 days after treatment initiation) and significant decrease in tumor cell proliferation in recurrent but not in primary tumors. Thus, our results show that the stromal compartment and the response to antiangionenic therapy of primary and in-field recurrent tumors are significantly different. Our findings suggest that antiangiogenic agents could be effective in the treatment of patients with relapses after radiotherapy.

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Section: Resultssupporting

confidence: 76%

Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti–Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors

et al. 2007

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“…PlGF levels in plasma and tumors correlate with tumor stage, vascularity, recurrence, metastasis and survival in various tumors (48,49). Of note, PlGF is up-regulated after anti-VEGF therapy and gemcitabine (26,50,51). These findings point to a role for PlGF in rapid restoration of tumor blood supply after treatment and thus, to enhanced likelihood of tumor regrowth.…”

Section: Discussionmentioning

confidence: 94%

Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: An experimental study with a multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy

Casneuf

Demetter²,

Boterberg³

et al. 2009

Oncol Rep

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Abstract. This work evaluated SU11248 (sunitinib) as a potential therapeutic agent, alone or in combination with the cytotoxic agent gemcitabine or radiotherapy in a murine model of pancreatic cancer. Panc02 cells were injected subcutaneously into HsdOla/MF1 mice (n=222). Treatment was administered during 1 week: sunitinib (SUN), gemcitabine (GEM), radiotherapy (RT), RT+SUN and GEM+SUN. Mice were sacrificed 14 days after treatment. The effect on microvessel density (MVD) was measured by CD31 staining. Apoptosis (sFAS, cleaved caspase-3) and proangiogenic proteins (VEGF, PlGF, EGF) were measured with ELISA and immunohistochemistry. At day 14, tumors in all groups increased significantly despite treatment. Only after RT/SUN treatment tumor growth slowed down, although the accretion was still significant (P=0.033). Highest levels of apoptosis were seen in GEM/SUN, RT/SUN and RT treated mice (respectively P<0.001, P<0.01 and P<0.05 compared to placebo). MVD was lowest in RT/SUN treated mice [compared to placebo (P<0.05), GEM (P<0.05) and GEM/SUN (P<0.01)]. Highest VEGF levels were seen after RT and RT/SUN treatment [vs. placebo (P<0.001) and vs. other treatments (P<0.01 for all comparisons)]. GEM and SUN in monotherapy lead to an up-regulation of PlGF and EGF, respectively. In conclusion, the combination treatments RT/SUN and GEM/SUN result in a more potent antiangiogenic and antitumor effect when compared to either treatment alone. Multitargeted angiogenesis inhibitor therapy with sunitinib combined with either radiotherapy or gemcitabine may be a novel approach for human pancreatic cancer.

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“…PlGF is associated with early recurrence of hepatocellular carcinoma following radical resection and was upregulated in preclinical lung and colon adenocarcinoma tumors following radioimmunotherapy (24,25). In colorectal cancer patients with metastatic disease, PlGF levels increased following the administration of bevacizumab in combination with chemotherapy and/or radiation (26,27).…”

Section: Introductionmentioning

confidence: 99%

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Ren¹,

Weber²,

Yao³

et al. 2011

Clinical Cancer Research

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Purpose: Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models. Experimental Design: Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA. Results: Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non–tumor-bearing mice. Conclusion: With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others. Clin Cancer Res; 17(5); 976–88. ©2011 AACR.

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Altered tumor vessel maturation and proliferation in placenta growth factor‐producing tumors: Potential relationship to post‐therapy tumor angiogenesis and recurrence

Cited by 57 publications

References 17 publications

Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti–Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors

Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti–Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors

Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: An experimental study with a multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

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