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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Implications of vessel co-option in sorafenib-resistant hepatocellular carcinoma
Elizabeth A Kuczynski1, Robert S Kerbel2
1Sunnybrook Research Institute, 2075 Bayview Avenue, S-Wing, Room S217, Toronto, ON, M4N 3M5, Canada.
Abstract:
The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma (HCC) where alternate therapies are lacking. We recently published a paper entitled "Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma" in the Journal of the National Cancer Institute, providing a potential explanation for this limited benefit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment.
Insights
Tumors resist anti-angiogenic drugs by hijacking liver blood vessels instead of growing new ones. This vessel co-option mechanism explains limited treatment benefits for hepatocellular carcinoma (HCC).
Area of Science:
- Oncology
- Vascular Biology
- Hepatocellular Carcinoma Research
Background:
- Limited and transient responses to anti-angiogenic therapy present a significant challenge in treating advanced hepatocellular carcinoma (HCC).
- Understanding the mechanisms behind acquired resistance to therapies like sorafenib is crucial for developing effective treatments for HCC.
Purpose of the Study:
- To investigate the underlying mechanisms of acquired resistance to sorafenib in hepatocellular carcinoma (HCC).
- To determine whether tumor growth relies on sprouting angiogenesis or vessel co-option in sorafenib-resistant HCC.
Main Methods:
- Utilized a mouse model of hepatocellular carcinoma (HCC) that had acquired resistance to sorafenib.
- Analyzed tumor vascularization strategies, comparing angiogenesis (new vessel growth) with vessel co-option (utilization of existing vasculature).
- Assessed tumor invasiveness in relation to vascularization patterns.
Main Results:
- Sorafenib-resistant HCC tumors in mice shifted from angiogenesis to co-opting existing liver vasculature.
- Increased tumor invasiveness was associated with the switch to vessel co-option.
- This mechanism of vessel co-option may be relevant to other human tumor types.
Conclusions:
- Acquired resistance to sorafenib in HCC is driven by tumor co-option of the liver vasculature, not by sprouting angiogenesis.
- Vessel co-option represents a key mechanism for tumor adaptation and resistance to anti-angiogenic therapy.
- The findings have significant implications for the clinical application of anti-angiogenic agents in cancer treatment, particularly for HCC.
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