Lei Xu, MD, PhD
Assistant Professor of Radiation Oncology
Harvard Medical School
Edwin L. Steele Laboratory for Tumor Biology
Molecular Mechanisms for the Regulation of Angiogenic Gene Expression by the Tumor Microenvironment
As part of the Edwin L. Steele Laboratory for Tumor Biology, the primary research focus at the Xu Laboratory is on the role and the molecular mechanism of tumor-host interaction in tumor angiogenesis and metastasis. The process of cancer metastasis consists of a long series of sequential, interrelated steps. The outcome of the process is dependent on both the intrinsic properties of the tumor cells and the responses of the host. Hypoxia and acidic pH are common features of solid tumors. Recently we discovered for the first time that tumor acidic microenvironment up-regulates the expression of an angiogenic factor, VEGF, via the ERK1/2 MAPK pathway. Subsequently, we showed that tumor hypoxia up-regulates another angiogenic factor, interleukin 8, via the PI3K/Akt pathway. One of the major obstacles to antiangiogenic therapy is that malignant tumors become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules. By using cDNA microarrays, we demonstrated that herceptin modulates the expression of multiple pro- and anti-angiogenic factors, leading to the normalization and regression of the vasculature in experimental human breast tumors. By using molecules like herceptin to target many angiogenic factors at once, we may improve the success rate of antiangiogenic therapy.
Function And Regulation of PlGF
PIGF, a VEGF family member, has been shown to contribute to angiogenesis under pathological conditions, and is involved in tumor angiogenesis. However, the exact function of PlGF is unknown, and the exact mechanism of its expression regulation is not understood. Our preliminary data show that several tumor cell lines express PlGF in vitro. PlGF expression is decreased in tumor xenografts when compared to tumor cells in culture, indicating that the tumor microenvironment regulates PlGF expression. Furthermore, we have shown that physiological stimuli (such as hypoxia and ROS), inflammatory cytokines, and chemotherapeutic agents regulate PlGF expression. We are currently investigating the function of PlGF in tumor angiogenesis and metastasis and studying the molecular mechanism of PlGF expression regulation. By understanding the biological function and regulation of PlGF in tumor progression, we will be able to design new antiangiogenic cancer therapies.