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Effect of p53 status on tumor response to antiangiogenic therapy
Joanne L Yu1, Janusz W Rak, Brenda L Coomber
1Sunnybrook and Women's College Health Sciences Centre, Molecular and Cellular Biology Research, Room S-218, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
Abstract:
The p53 tumor suppressor gene is inactivated in the majority of human cancers. Tumor cells deficient in p53 display a diminished rate of apoptosis under hypoxic conditions, a circumstance that might reduce their reliance on vascular supply, and hence their responsiveness to antiangiogenic therapy. Here, we report that mice bearing tumors derived from p53(-/-) HCT116 human colorectal cancer cells were less responsive to antiangiogenic combination therapy than mice bearing isogenic p53(+/+) tumors. Thus, although antiangiogenic therapy targets genetically stable endothelial cells in the tumor vasculature, genetic alterations that decrease the vascular dependence of tumor cells can influence the therapeutic response of tumors to this therapy.
Insights
Tumor cells lacking the p53 gene show reduced apoptosis and respond poorly to antiangiogenic therapy. This highlights how tumor cell genetics can impact treatment effectiveness, even when targeting tumor vasculature.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- The p53 tumor suppressor gene is frequently inactivated in human cancers.
- p53-deficient tumors exhibit reduced apoptosis under hypoxia, potentially decreasing vascular dependence.
- This reduced vascular dependence may confer resistance to antiangiogenic therapies.
Purpose of the Study:
- To investigate the impact of p53 deficiency on tumor response to antiangiogenic combination therapy.
- To determine if reduced vascular dependence in p53-deficient tumors affects therapeutic outcomes.
Main Methods:
- Utilized isogenic HCT116 human colorectal cancer cell lines with and without p53 (p53(-/-) vs. p53(+/+)).
- Administered antiangiogenic combination therapy to mice bearing these tumors.
- Assessed and compared tumor responsiveness to therapy between the two groups.
Main Results:
- Mice with p53(-/-) HCT116 tumors showed significantly less responsiveness to antiangiogenic combination therapy compared to mice with p53(+/+) tumors.
- This suggests that p53 deficiency influences tumor sensitivity to therapies targeting tumor vasculature.
Conclusions:
- Genetic alterations, such as p53 inactivation, that decrease tumor cell vascular dependence can modulate therapeutic response.
- While antiangiogenic therapy targets endothelial cells, the intrinsic genetic makeup of tumor cells plays a crucial role in treatment efficacy.
- Understanding p53 status may be important for predicting response to antiangiogenic strategies.
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