Targeting Redundant ROBO1 and SDF-1 Pathways Prevents Adult Hemangioblast Derived-EPC and CEC Activity Effectively
Anitha K Shenoy1,2, Liya Pi1,3, Alexander P Ligocki1,2
1Program in Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
Abstract:
Neovascularization is a key therapeutic target for cancer treatment. However, anti-angiogenic therapies have shown modest success, as tumors develop rapid resistance to treatment owing to activation of redundant pathways that aid vascularization. We hypothesized that simultaneously targeting different pathways of neovascularization will circumvent the current issue of drug resistance and offer enhanced therapeutic benefits. To test this hypothesis, we made use of two distinct models of tumor-neovascularization, which exhibit equally dense microvasculature but show disparate sensitivity to anti-SDF-1 treatment. Lewis lung carcinoma (LLC) is primarily a vasculogenic-tumor that is associated with HSC functioning as a hemangioblast to generate circulating Endothelial Progenitor Cells contributing to formation of new blood vessels, and responds to anti-SDF-1 treatment. B16F0 melanoma is an angiogenic-tumor that derives new blood vessels from existing vasculature and is resistant to anti-SDF-1 therapy. In this study, we observed increased expression of the angiogenic-factor, Robo1 predominantly expressed on the blood vessels of B16F0 tumor. Blockade of Robo1 by the decoy receptor, RoboN, resulted in reduced microvascular-density and tumor-growth. However, this was associated with mobilization of BM-cells into the B16F0 tumor, thus switching the mode of neovascularization from angiogenic to vasculogenic. The use of a combinatorial treatment of RoboN and the monoclonal anti-SDF-1 antibody effectively attenuated tumor-growth and inhibited both angiogenic and BM-derived microvessels.
Insights
Targeting cancer neovascularization with combined therapies overcomes drug resistance. Simultaneous blockade of Robo1 and SDF-1 pathways effectively inhibits tumor growth by targeting both angiogenic and bone marrow-derived vessels.
Area of Science:
- Oncology
- Cancer Biology
- Angiogenesis Research
Background:
- Neovascularization is crucial for tumor growth and a target for cancer therapy.
- Existing anti-angiogenic therapies face challenges due to tumor resistance mediated by redundant vascularization pathways.
- Tumor vascularization can occur through angiogenesis (from existing vessels) or vasculogenesis (from bone marrow-derived cells).
Purpose of the Study:
- To investigate the efficacy of simultaneously targeting distinct neovascularization pathways to overcome drug resistance in cancer.
- To compare the response of vasculogenic (Lewis lung carcinoma, LLC) and angiogenic (B16F0 melanoma) tumors to anti-angiogenic treatments.
- To evaluate the potential of a combinatorial therapy involving Robo1 blockade and anti-SDF-1 treatment.
Main Methods:
- Utilized two distinct tumor models: LLC (vasculogenic) and B16F0 melanoma (angiogenic).
- Administered anti-SDF-1 treatment to assess differential tumor sensitivity.
- Blocked the angiogenic factor Robo1 using its decoy receptor, RoboN.
- Investigated the effect of RoboN treatment on microvascular density, tumor growth, and bone marrow cell mobilization.
- Assessed the impact of a combination therapy using RoboN and anti-SDF-1 antibody.
Main Results:
- B16F0 melanoma tumors showed increased expression of the angiogenic factor Robo1.
- Blockade of Robo1 reduced microvascular density and tumor growth in B16F0 melanoma.
- Robo1 blockade induced bone marrow cell mobilization into B16F0 tumors, shifting neovascularization to a vasculogenic mode.
- Combined treatment with RoboN and anti-SDF-1 antibody significantly attenuated tumor growth.
- The combinatorial therapy effectively inhibited both angiogenic and bone marrow-derived microvessels.
Conclusions:
- Simultaneous targeting of distinct neovascularization pathways can overcome therapeutic resistance in cancer.
- Combinatorial therapy using RoboN and anti-SDF-1 antibody demonstrates potent anti-tumor effects by inhibiting multiple vascularization mechanisms.
- This dual-targeting strategy offers a promising approach to enhance therapeutic benefits in cancer treatment by preventing adaptive resistance.
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