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Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary
O Melnyk1, M A Shuman, K J Kim
1Cancer Research Institute, University of California, San Francisco 94143, USA.
Abstract:
Tumor growth is dependent on new blood vessel formation. Inhibition of vascular endothelial growth factor (VEGF), an endothelial cell mitogen and angiogenic factor secreted by a variety of tumors and tumor cell lines, is sufficient to inhibit primary tumor growth. In the present study, we examined the effect of inhibiting VEGF on tumor cell micrometastasis. A transfectant of A431 (a human epidermoid carcinoma cell line) expressing chloramphenicol acetyltransferase (CAT) was injected s.c. into severe combined immunodeficiency (scid) mice, which were then sacrificed after 6 weeks. The presence of A431 metastases at distant sites was demonstrated by detection of CAT activity in whole-organ lysates. Treatment of animals with VEGF-neutralizing antibodies not only inhibited primary tumor growth but also suppressed metastases, as determined by CAT activity in organ lysates. In experiments to determine the mechanism by which anti-VEGF antibody inhibited metastasis, control animals were sacrificed when their tumors had reached the same size as tumors in VEGF antibody-treated animals. Metastases were uniformly present in these control animals. These findings show that inhibition of VEGF alone is sufficient to prevent tumor growth and dissemination in vivo. The inhibitory effect on metastases appears to be distinct from that on primary tumor growth.
Insights
Inhibiting vascular endothelial growth factor (VEGF) stops primary tumor growth and prevents cancer spread. This study shows anti-VEGF therapy is effective against tumor dissemination and primary tumor development.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Tumor growth relies on new blood vessel formation.
- Vascular Endothelial Growth Factor (VEGF) is a key factor in angiogenesis and is secreted by tumors.
- Inhibiting VEGF has shown potential in controlling primary tumor growth.
Purpose of the Study:
- To investigate the effect of inhibiting VEGF on tumor cell micrometastasis.
- To determine if anti-VEGF therapy can prevent cancer dissemination.
Main Methods:
- A431 human epidermoid carcinoma cells were injected into immunodeficient mice.
- Tumor growth and metastasis were monitored in mice treated with VEGF-neutralizing antibodies.
- Chloramphenicol acetyltransferase (CAT) activity was used to detect A431 cells in distant organs.
Main Results:
- VEGF-neutralizing antibodies significantly inhibited primary tumor growth.
- Treatment with anti-VEGF antibodies suppressed the formation of metastases at distant sites.
- Metastases were present in control animals even when tumors reached similar sizes, indicating a specific effect on dissemination.
Conclusions:
- Inhibition of VEGF alone is sufficient to prevent both tumor growth and dissemination in vivo.
- The anti-metastatic effect of anti-VEGF antibodies appears to be distinct from its effect on primary tumor growth.
- Targeting VEGF is a promising strategy for controlling cancer progression and metastasis.