Laboratory of John D. Allendorf, MD
Principal Investigator
John D. Allendorf, MD
Background for Research focus:
Two thirds of patients undergoing liver resection for metastatic colon cancer will succumb to the disease, underscoring the need to develop novel treatment strategies. The regenerative properties of the liver remnant have been associated with increased tumor cell proliferation. The intersection of the signaling pathways common to both tumor growth and liver regeneration may provide targets that can be exploited to better treat patients undergoing resection of liver metastases. One such molecular target is the receptor for advanced glycation endproducts (RAGE), which has been implicated in tumor proliferation and has been shown to be protective in models of liver injury.
Based on considerable preliminary data and a growing understanding of RAGE signaling pathways, we hypothesize that RAGE blockade will suppress tumor growth in the liver remnant.
Main Focus of the Laboratory:
Basic science investigations are focused on evaluating the role of the RAGE proinflammatory pathway in tumor proliferation. Specifically, we have designed animal models 1) to determine if pharmacologic RAGE blockade suppresses the growth of colorectal liver metastases in the setting of partial hepatectomy, 2) to evaluate the contribution of RAGE signaling in the host tissues to the increase in tumor growth observed following partial hepatectomy (by genetically manipulating the host), and 3) to evaluate the contribution of tumor cell specific RAGE signaling to the increase in tumor growth observed after partial hepatectomy (by genetically altering the tumor cells).
We are also interested in exploring the potential role of RAGE in carcinogenesis. Using transgenic mouse models of hepatocellular carcinoma and intestinal adenocarcinoma, we are testing the impact of RAGE signaling on tumor development.
Current Projects:
- Evaluation of the effects of partial hepatectomy on the progression of metastatic colorectal adenocarcinoma.
- Evaluation of the effects of RAGE blockade on the progression of colorectal liver metastases in the setting of partial hepatectomy.
- Evaluation of the growth of colorectal liver metastases in RAGE knockout and RAGE transgenic mice.
- Evaluation of the growth of colorectal cancer cells transfected with functional and dysfunctional RAGE constructs in wildtype mice.
- Breeding experiments designed to evaluate the effects of RAGE on tumorigenesis in mice that are genetically altered to spontaneously develop primary liver or bowel cancer.
- Evaluation of human pancreatic cancer specimens for expression of novel tumor associated antigens.
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