Axillary radiation with surgery in breast cancer patients often leads to lymphedema, which affects nearly 400,000 women in the United States. Lymphedema is disfiguring, painful and forms a nidus for infection. As current treatments provide little relief for many patients, it is critical to develop methods to prevent and reverse the formation of lymphedema. The use of lymphangiogenic growth factors to spur lymphatic growth and reverse lymphedema has been advocated. However, in cancer patients this strategy may facilitate the further spread of cancer cells. To avoid this complication, we focus on lymphedema prevention in this Pathway to Independence Award. While information on the radiosensitivity of many tissues Is available, the effects of radiation on lymphatic vessels have been largely unreported. In this proposal we will study the radiosensitivity of lymphatic endothelial cells and their cellular and molecular response to radiation. We will then alter lymphatic endothelial cell radiosensitivity through exposure to growth factors or genetic manipulation of growth factor signaling. We will complement these studies by measuring the radiosensitivity of normal and proliferating lymphatic vessels In vivo. Finally, we will prevent radiation-induced damage of lymphangiogenic vessels by administering inhibitors of lymphatic growth factor receptors. The ultimate goal of this project is to identify strategies to protect lymphatic vessels from radiation-induced damage in order to prevent lymphedema in patients. I will complete this worl

Public Health Relevance

;Nearly 400,000 breast cancer patients in the United States develop lymphedema after axillary radiation. Lymphedema treatments are generally designed to control swelling and minimize pain associated with lymphedema, but these treatments are only marginally effective. Understanding the response of lymphatic vessels to radiation wili allow strategies to prevent lymphedema in breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA137167-04
Application #
8326221
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mohla, Suresh
Project Start
2008-09-12
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$237,531
Indirect Cost
$101,084
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Padera, Timothy P; Meijer, Eelco F J; Munn, Lance L (2016) The Lymphatic System in Disease Processes and Cancer Progression. Annu Rev Biomed Eng 18:125-58
Jeong, Han-Sin; Jones, Dennis; Liao, Shan et al. (2015) Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. J Natl Cancer Inst 107:
Pereira, Ethel R; Jones, Dennis; Jung, Keehoon et al. (2015) The lymph node microenvironment and its role in the progression of metastatic cancer. Semin Cell Dev Biol 38:98-105
Kunert, Christian; Baish, James W; Liao, Shan et al. (2015) Mechanobiological oscillators control lymph flow. Proc Natl Acad Sci U S A 112:10938-43
Kuo, Angera H; Ancukiewicz, Marek; Kozak, Kevin R et al. (2015) Cardiac and inflammatory biomarkers do not correlate with volume of heart or lung receiving radiation. Radiat Oncol 10:5
Kesler, Cristina T; Pereira, Ethel R; Cui, Cheryl H et al. (2015) Angiopoietin-4 increases permeability of blood vessels and promotes lymphatic dilation. FASEB J 29:3668-77
Hagendoorn, Jeroen; Yock, Torunn I; Borel Rinkes, Inne H M et al. (2014) Novel molecular pathways in Gorham disease: implications for treatment. Pediatr Blood Cancer 61:401-6
Liao, Shan; Jones, Dennis; Cheng, Gang et al. (2014) Method for the quantitative measurement of collecting lymphatic vessel contraction in mice. J Biol Methods 1:
Munn, Lance L; Padera, Timothy P (2014) Imaging the lymphatic system. Microvasc Res 96:55-63
Kesler, Cristina T; Liao, Shan; Munn, Lance L et al. (2013) Lymphatic vessels in health and disease. Wiley Interdiscip Rev Syst Biol Med 5:111-24

Showing the most recent 10 out of 16 publications