Professor, Dept. of Pharm. and Cancer Biology Duke University Medical Center
Donald and Elizabeth Cooke Professor of Experimental Oncology, Duke University
Fellow of American Association for the Advancement of Science
Hepatocellular carcinoma (HCC) intrahepatic metastases, including portal vein tumor thrombus (PVTT), are strongly correlated to poor prognosis of patients. However, the pathogenesis of this clinic symptom remains elusive. To address this question, we uncovered a TGF-ß signaling pathway through which the microenvironment of liver tissue around the portal vein is likely altered by the recruitment of T regulatory (Treg) cells to suppress immune surveillance, consequently creating a condition to enhance the formation of PVTT. Mechanistically, this is achieved by the down-regulation of miR-34a, resulting in the enhanced production of chemokine CCL22, a known factor for Treg cell recruitment. Those findings reveal a critical role for the immune-subversive nature of the microenvironment for the development of HCC intrahepatic metastasis and the potential of CCL22 as a therapeutic target for this disease.
In a separate study, we have found that a pair of microRNA, miR-126/miR-126* whose down-regulation is associated with poor prognosis in human breast cancers, act to suppress the recruitment of mesenchymal stem cells (MSCs) and inflammatory monocytes into the tumor stroma through both direct and indirect mechanisms reducing the production of SDF-1 and CCL2, consequently inhibiting lung metastasis by breast tumor cells in a mouse xenograft model. Taken together, we have identified a novel mechanism by which two tumor suppressive microRNAs derived from one single transcript regulate the composition of tumor microenvironment via recruitment of two types of cells by different mechanisms to inhibit breast cancer metastasis.
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