Tumor angiogenesis: Better vessels, better therapy
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Rgs5-mediated inhibition of G-protein signaling results in a more mature tumor vasculature, which increases the effectiveness of T-cell immunotherapy in tumors.
Tumor vasculature is less organized and more fragile than that of normal tissue. The altered vessel architecture is chiefly caused by abnormal pericytes and endothelial cells, and hinders the infiltration of immune cells into the tumor. Little is known about why these pericytes and endothelial cells are abnormal. Hamzah et al. now report in Nature that vascular abnormalities present in mouse pancreatic tumors are caused by Rgs5 (regulator of G-protein signaling 5), which is a known GTPase-activating marker for pericyte progenitor cells.
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Hamzah et al. noted that the life span of RIP1–Tag5 mice — which develop pancreatic tumors expressing defined T-antigens (TAGs) — was reduced when the mice lacked Rgs5 (RIP1–Tag5 X Rgs5-/- mice). This appeared to be related to the fact that RIP1–Tag5 X Rgs5-/- mice displayed more normal vessel architecture, which led to both better oxygen supply to tumors and reduced vascular permeability. Cytological examination of the RIP1–Tag5 X Rgs5-/- vessels showed a more mature pericyte phenotype as indicated by expression of αSMA (α-smooth muscle actin) and NG2. The connection between Rgs5 and vessel stability was also demonstrated by the finding that Rgs5-/- mice had less brain edema after induction of cerebral ischemia than wild-type mice.
But how could Rgs inhibition be used therapeutically if tumors appear to thrive in Rgs5-/- mice? Hamzah et al. primed CD4+ and CD8+ T cells ex vivo against TAG epitopes from RIP1–Tag5 X Rgs5-/- tumors. After these were transferred back into the mice, the authors observed an increase in the presence of T cells in the tumor parenchyme, which led to a strong anti-tumor immune response. This indicated that the more normal vessel architecture of RIP1–Tag5 X Rgs5-/- mice allowed T cells to infiltrate the tumors more readily than in RIP1–Tag5 mice. Indeed, the medium life span of RIP1–Tag5 X Rgs5-/- mice receiving primed T cells was increased by one third.
The current study bears some similarity to work showing that VEGF (vascular endothelial growth factor) inhibition initially leads to a more normal vessel architecture due to increased pericyte density, but at the same time it confers higher drug susceptibility to the tumors. An anti-G-protein signaling approach as presented here may prevent the development of therapeutic resistance caused by the expression of other angiogenic factors. Furthermore, the fact that Rgs5 is expressed in many tumors encourages a more detailed exploration of the mechanism and the pharmacologic potential of anti-G-protein signaling-based strategies.
Mirko von Elstermann
Functional Glycomics Gateway
Reference
- Hamzah J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410-414 (2008) | Article | PubMed |
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