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CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis
A C Prats1, L Van den Berghe, A Rayssac
1Université de Toulouse, UPS, TRADGENE, EA4554, F-31432 Toulouse, France.
Abstract:
Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies.
Insights
Fibrinogen-binding protein 4 (fibstatin) and Platelet Factor-4 variant 1 (CXCL4L1) synergistically inhibit tumor angiogenesis, lymphangiogenesis, and metastasis. This combination therapy shows promise for developing novel anti-metastasis gene therapies.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Tumor growth and metastasis depend on angiogenesis and lymphangiogenesis.
- Tumors develop compensatory mechanisms to overcome single anti-angiogenic or anti-lymphangiogenic therapies.
- Combined anti-(lymph)angiogenic strategies are needed to effectively inhibit tumor cell invasion.
Purpose of the Study:
- To investigate the cooperative anti-tumor effects of endogenous anti-angiogenic molecules (endostatin, fibstatin) and the chemokine CXCL4L1.
- To evaluate the efficacy of co-expressing these molecules using IRES-based bicistronic vectors for local and distant delivery.
- To determine the synergistic potential of fibstatin and CXCL4L1 in inhibiting tumor progression and metastasis.
Main Methods:
- Co-expression of fibstatin and CXCL4L1 using IRES-based bicistronic vectors.
- Local delivery via lentiviral transduction of pancreatic adenocarcinoma cells.
- Distant delivery via adeno-associated virus (AAV) intramuscular administration followed by subcutaneous tumor injection.
- In vitro assessment of endothelial cell proliferation, migration, and tubulogenesis.
- In vivo evaluation of angiogenesis, lymphangiogenesis, and metastasis to lymph nodes.
Main Results:
- Finstatin and CXCL4L1 demonstrated synergistic inhibition of endothelial cell proliferation, migration, and tubulogenesis in vitro.
- No synergistic effect was observed for the fibstatin-endostatin combination.
- Finstatin and CXCL4L1 significantly inhibited in vivo angiogenesis and lymphangiogenesis.
- The combination of fibstatin and CXCL4L1 suppressed tumor spread to lymph nodes.
- No significant improvement in tumor growth inhibition was observed with the combined molecules compared to single agents.
Conclusions:
- Finstatin and CXCL4L1 exhibit a synergistic effect in inhibiting tumor angiogenesis, lymphangiogenesis, and metastasis.
- IRES-based vectors are a viable platform for developing combined gene therapies against metastasis.
- Targeting both angiogenesis and lymphangiogenesis with fibstatin and CXCL4L1 offers a promising strategy for anti-metastasis treatment.
