An Intradermal Assay for Quantification and Kinetics Studies of Tumor Angiogenesis in Mice

Runkel, Sanyukta; Hunter, Nancy; Milas, Luka

doi:10.2307/3577824

Cited by 29 publications

(15 citation statements)

References 13 publications

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“…A strong trend for a lower functional vessel density was also found in recurrent tumors. Our findings are similar to results obtained for tumors growing in preirradiated normal tissue, wherein a slower growth rate has been associated with a reduced vascular density and increased necrotic loss of nonirradiated cancer cells at a constant proliferation rate (4,12,15,16).…”

Section: Resultssupporting

confidence: 80%

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: 80%

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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“…Angiogenic potential was assessed in vivo using the intradermal angiogenesis assay (Kreisle and Ershler, 1988;Runkel et al, 1991). Adult female BALB/c-nu/nu mice, bred at our research institute, were used as test animals.…”

Section: Angiogenesismentioning

confidence: 99%

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Rofstad

Danielsen²

1998

Br J Cancer

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Summary Tumour cells exposed to hypoxia in vitro can show increased expression of several selected genes, including the gene encoding the vascular endothelial growth factor (VEGF), suggesting that hypoxia followed by reoxygenation might promote the malignant progression of tumours. An in vitro/in vivo study was conducted to investigate whether hypoxia can increase the angiogenic potential of tumour cells through increased VEGF secretion. Four human melanoma cell lines (A-07, D-12, R-18, U-25) were included in the study. Cell cultures were exposed to hypoxia (oxygen concentration <10 p.p.m.) in vitro using the steel chamber method. Rate of VEGF secretion was measured in vitro in aerobic and hypoxic cell cultures by ELISA. Angiogenesis was assessed in vivo using the intradermal angiogenesis assay. Aliquots of cells harvested from aerobic cultures or cultures exposed to hypoxia for 24 h were inoculated intradermally in the flanks of adult female BALB/cnu/nu mice. Tumours developed and angiogenesis was quantified by scoring the number of capillaries in the dermis oriented towards the tumours. The number of tumour-oriented capillaries did not differ significantly between tumours from hypoxic and aerobic cultures for A-07 and U-25, whereas tumours from hypoxic cultures showed a larger number of tumour-oriented capillaries than tumours from aerobic cultures for D-1 2 and R-1 8. The VEGF secretion under aerobic conditions and the absolute increase in VEGF secretion induced by hypoxia were lower for D-12 and R-18 than for A-07 and U-25, whereas the relative increase in VEGF secretion induced by hypoxia was higher for D-12 and R-18 than for A-07 and U-25. VEGF is not a limiting factor in the angiogenesis of some tumours under normoxic conditions. Hypoxia can increase the angiogenic potential of tumour cells by increasing the secretion of VEGF, but only of tumour cells showing low VEGF secretion under normoxia. Transient hypoxia might promote the malignant progression of tumours by temporarily increasing the angiogenic potential of tumour cells showing low VEGF expression under normoxic conditions. Keywords: angiogenesis; hypoxia; melanoma; vascularization; VEGF Many malignant tumours develop regions of hypoxic cells during growth (Coleman, 1988;Vaupel et al, 1989;Brown and Giaccia, 1994). Two types of hypoxia have been recognized: chronic hypoxia, arising from limitations in oxygen diffusion, and acute hypoxia, resulting from transient stoppages in microregional blood flow (Stone et al, 1993;Horsman, 1995). Reoxygenation of hypoxic cells occurs during unperturbed tumour growth as a result of reopening of temporarily closed vessels and during therapy as a result of therapy-induced tumour cell inactivation (Kallman, 1972;Brown, 1979;Chaplin et al, 1987). Hypoxia followed by reoxygenation might promote the malignant progression of tumours (Hill, 1990). Thus, tumour cells exposed to hypoxia in vitro can show increased expression of several selected genes, including genes encoding cell cycle-regulatory proteins, haematopoietic...

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“…Tumor angiogenesis was assessed as previously described (54)(55)(56). 4T1 clones (EV, R, and RL) were cultured and harvested when they were in exponential growth.…”

Section: Intradermal Tumor Angiogenesis Assaymentioning

confidence: 99%

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

Venkatesha

Hanai

Seth

et al. 2006

Molecular Cancer Research

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Lipocalin 2 is an iron-binding secreted protein that converts embryonic kidney mesenchyme to epithelia. Previously, we reported that lipocalin 2 could revert 4T1-ras-transformed mesenchymal tumor cells to a more epithelial phenotype, increase E-cadherin expression, and suppress cell invasiveness in vitro and in vivo, indicating that lipocalin 2 is a metastasis suppressor. Here, we show that lipocalin 2 can suppress the ras-induced expression of vascular endothelial growth factor in 4T1 cells via down-regulation of ras mitogenactivated protein kinase and ras phosphatidylinositol-3-kinase signaling. In addition, the expression of thrombospondin-1 (an antiangiogenic molecule) was increased in tumors formed by 4T1-ras cells into which lipocalin 2 was stably introduced. Tumor angiogenesis, assessed via an intradermal tumor angiogenesis assay, was also suppressed by lipocalin 2. We also show that caveolin-1 is a critical mediator of this activity. These data provide new insights into the action of lipocalin 2 and raise the possibility that the administration of lipocalin 2 may be useful for inhibiting tumor angiogenesis, in addition to suppressing tumor metastasis, in cancers which show ras activation. (Mol Cancer Res 2006;4(11):821 -9)

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An Intradermal Assay for Quantification and Kinetics Studies of Tumor Angiogenesis in Mice

Cited by 29 publications

References 13 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

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma

Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells

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