Molecular Determinants of Tumor Progression in A Steatolic Liver Microenvironment

Summary

Principal Investigator: Harold L Moses
Abstract: DESCRIPTION (provided by applicant): Obesity has been associated with increased incidence of malignancies including colon cancer. As the epidemics of obesity and associated diabetes and metabolic syndrome continue to grow, it is clinically relevant to understand the influence that a steatotic (fatty) liver microenvironment has on the growth of tumors;both metastatic and primary. Preliminary studies show an increased burden of metastatic disease in a mouse model of diet-induced non-alcoholic fatty liver disease (NAFLD). Microarray analysis indicates that the matrix metalloproteinases MMP12 and MMP13 are markedly elevated in the steatotic microenvironment, leading to the hypothesis that tumor cells react to an enhanced host tissue MMP response in the microenvironment of hepatite steatosis and steatohepatitis, which in turn plays a role in dictating the biological behavior of the tumor at its site of metastasis. To test this hypothesis, the specific aims of this proposal utilize mouse models of NAFLD as well as experimental liver metastasis models. In vivo techniques of bone marrow and liver transplantation are proposed to examine cellular mechanisms of action of these MMPs. These are coupled with sophisticated multiphoton microscopy techniques that allow visualization of early metastases in intact mouse livers and analysis of interactions of these tumor cells with the liver microenvironment. Finally, this proposal seeks to determine the molecular mechanisms by which MMP12 and/or MMP13 influences metastatic efficiency in the steatotic liver microenvironment. We hypothesize that MMP-mediated proteolysis of cytokines, chemokines, and/or adipokines establishes microenvironmental cues that influence the survival and establishment of metastatic cancer cells in the steatotic liver. Findings in a mouse model will be corroborated with human liver tissue samples to assure relevance to human disease. The long term objective of these studies is to provide information on the molecular events that contribute to the establishment of colon carcinoma metastasis in the fatty liver that will then lead to more refined targeted therapeutic strategies for the treatment of metastatic colorectal cancer. As a greater percentage of the population lives with NAFLDi the impact of this microenvironment on the growth of metastatic tumors must be better understood. The combination of selective inhibition of stromal and epithelial derived MMPs may become part of rational strategies to treat metastatic colorectal cancer. RELEVANCE (See Instructions): 7 The rising incidence of non alcoholic fatty liver disease (NAFLD) associated with obesity is a problem of increasing clinical significance. In addition, obesity is clinically associated with an increased prevalence of certain malignancies including colon cancer and breast cancer. This proposal seeks to probe the molecular mechanisms by which microenvironmental liver steatosis and steatohepatitis impacts metastasis of colorectal cancer cells to the liver.
Funding Period: 2009-09-29 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Molecular pathways: adiponectin and leptin signaling in cancer
    Michael N VanSaun
    Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Clin Cancer Res 19:1926-32. 2013
  2. pmc Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease
    Michael N VanSaun
    Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 8:e73054. 2013

Research Grants

  1. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
  2. Myofibroblasts in Gastrointestinal Cancers
    TIMOTHY CRAGIN WANG; Fiscal Year: 2013
  3. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
  5. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
  6. Mechanisms and Markers of Prostate Cancer Metastases
    ROBERT LOUIS VESSELLA; Fiscal Year: 2013
  7. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  8. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
  9. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  10. DRUG DEPENDENCE CLINICAL RESEARCH PROGRAM
    Reese T Jones; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Molecular pathways: adiponectin and leptin signaling in cancer
    Michael N VanSaun
    Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Clin Cancer Res 19:1926-32. 2013
    ..This review addresses the current level of understanding of molecular pathways activated by adiponectin and leptin to identify the areas of intervention and facilitate advancement in the field...
  2. pmc Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease
    Michael N VanSaun
    Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
    PLoS ONE 8:e73054. 2013
    ..This increased hepatocellular proliferation and turnover in the setting of steatosis may play important roles in the progression and complications of NAFLD. ..

Research Grants30

  1. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  2. Myofibroblasts in Gastrointestinal Cancers
    TIMOTHY CRAGIN WANG; Fiscal Year: 2013
    ..The three projects are highly translational with heavy use of human tissues and physiological mouse models of digestive cancers, and are linked to a Phase 1 clinical trial in human patients with pancreatic cancer. ..
  3. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  4. ROLES AND REGULATION OF P53
    Carol Prives; Fiscal Year: 2013
    ..The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program. ..
  5. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
    ..In summary, we have shaped ICMIC-3 to closely adhere to the goals of PAR 09-157. ..
  6. Mechanisms and Markers of Prostate Cancer Metastases
    ROBERT LOUIS VESSELLA; Fiscal Year: 2013
    ..It also conducts pre-clinical xenograft studies and provides statistical support to the overall P01 program. Core B is the Administrative Core which provides overall administrative support to the investigators. ..
  7. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  8. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
    ..Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications. ..
  9. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  10. DRUG DEPENDENCE CLINICAL RESEARCH PROGRAM
    Reese T Jones; Fiscal Year: 2013
    ..abstract_text> ..
  11. Biology and Therapy of High Risk Neuroblastoma
    ROBERT CHARLES SEEGER; Fiscal Year: 2013
    ..nant.org), which includes 15 pediatric oncology institutions across the US and in Canada. ..
  12. DF/HCC Kidney Cancer SPORE
    David McDermott; Fiscal Year: 2013
    ..The overall goal of the DF/HCC Kidney Cancer SPORE is the translation of biological and technological advances into clinically meaningful advances for patients with kidney cancer. ..
  13. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..