Timothy P. Padera, PhD
Assistant Professor in Radiation Oncology
Harvard Medical School
Assistant in Biology
Edwin L. Steele Laboratory for Tumor Biology
As part of the Edwin L. Steele Laboratory for Tumor Biology, the Padera Laboratory examines pathophysiology of tumor associated lymphatic vessels and lymphatic metastasis. Lymphatic vessels are responsible for draining interstitial fluid from tissues and for transporting immune cells to lymph nodes to maintain the bodys immune surveillance. Lymphatic vessels also facilitate the dissemination of cancer cells from a primary tumor to regional lymph nodes. The mechanisms used by cancer cells to form lymph node metastasis are starting to be understood, with the hope of identifying treatment strategies to lower mortality due to disseminated cancer. In contrast to hematogenous metastasis in which the primary tumor has functional blood vessels for cancer cells to invade, the story for lymphatic metastasis is likely more complicated. Solid tumors seem to lack functional intratumor lymphatic vessels which means tumor cells that enter intratumor lymphatic vessels will not be carried by lymph flow to lymph nodes. Functional lymphatic vessels in the margin of tumors, however, seem sufficient for lymphatic metastasis to occur.
Using intravital microscopy, we have investigated the individual steps of lymphatic metastasis. We can monitor the lymphatic vessels in the tumor margin, observe tumor cells moving in lymphatic vessels, measure lymph flow and quantify the number of tumor cells that arrive in the draining lymph node. Our studies have shown that VEGF-C, which is associated with lymphatic metastasis in patients, increases the size of the tumor margin lymphatic vessels, making them more vulnerable to invasion. Our data suggests that VEGF-C needs to be blocked very early in the metastatic process to be able to reduce VEGF-C enhanced lymphatic metastasis.
In addition to our work on metastasis, we have studied mechanisms for the lack of functional lymphatic vessels in tumors. We have shown that the compressive mechanical forces generated by cancer cells proliferating in a confined space can cause the collapse of both blood and lymphatic vessels. The collapsed lymphatic vessels can no longer transport lymph and appear to be non-functional. This work highlights the importance of not only the biochemical but also the physical microenvironment in determining lymphatic structure and function.
Our future studies will continue to dissect the physical and molecular determinants of lymphatic vessel function, lymphangiogenesis and lymphatic metastasis. Through the use of our novel imaging technologies and animal models, we will answer timely questions that can lead to the development of treatments for lymphatic metastasis and lymphedema.