Abstract: FR-PO1009
TIMAP Drives Tumor Angiogenesis
Session Information
- Onco-Nephrology: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onco-Nephrology
- 1500 Onco-Nephrology
Authors
- Aburahes, Salah A., University of Alberta, Edmonton, Alberta, Canada
- Alavi, Parnian, University of Alberta, Edmonton, Alberta, Canada
- Rahman, Md. Mizanur, University of Alberta, Edmonton, Alberta, Canada
- Li, Laiji, University of Alberta, Edmonton, Alberta, Canada
- Ballermann, Barbara J., University of Alberta, Edmonton, Alberta, Canada
Background
TIMAP (TGFβ inhibited membrane associated protein) is an endothelial cell (EC)-predominant inhibitor of myosin phosphatase, which we first identified in glomerular EC. It is abundant in EC of developing, but not mature kidneys. Glomerular EC proliferation and sprouting angiogenesis in vitro require TIMAP. This study utilized the murine breast cancer model to determine whether in vivo angiogenesis also requires TIMAP.
Methods
Mouse mammary adenocarcinoma cells (E0771, syngeneic for C57BL/6 mice) were injected into mammary glands of 5 pairs of 8-week-old female TIMAP+/+ and TIMAP-/- mice (C57BL/6 background). Each pair was euthanized on the day the tumor diameter, determined by externally applied calipers, in one mouse of the pair exceeded 1.5 cm. The tumors were excised, their weight and mean diameter measured. Vascular density was quantified using fluorescence microscopy for the EC marker PECAM1.
Results
Tumor size was similar in TIMAP+/+ and TIMAP-/- mice through day 8-10. In 4 of 5 TIMAP-/-, but not TIMAP+/+ mice, the tumors then began to erode through the skin, bleed spontaneously and then regressed gradually. At the time of euthanasia (day 20-34 after injection) tumor size, weight and blood vessel density were significantly lower in TIMAP-/- compared to TIMAP+/+ mice (Table).
Conclusion
The data are interpreted to indicate that mammary tumors in TIMAP-/- become necrotic and then involute due to insufficient hypoxia-driven angiogenesis. The data furthermore indicate that TIMAP provides a critical pro-angiogenic signal in EC, at least during tumor angiogenesis. Further work is required to determine whether TIMAP could be targeted in the treatment of highly vascular tumors, including renal cell carcinoma.
Tumor Parameters
| TIMAP+/+ (n=5) | TIMAP-/-(n=5) | p (Student t-test) | |
| Mean Diameter (mm ± SD) | 18.24 ± 3.56 | 10.85 ± 2.73 | 0.006 |
| Mean Weight (g ± SD) | 2.59 ± 0.92 | 0.55 ± 0.43 | 0.002 |
| Vascular Density (arbitrary units ± SD) | 32.05 ± 6.82 | 20.65 ± 8.52 | 0.048 |
Funding
- Private Foundation Support