Targeting Ovarian Cancer Tumor Microenvironment Signaling for Therapeutic Effect
Abstract
A tumor is made not only of cancer cells, but rather cancer cells plus many other cell types. These other cells include supporting/stromal cells, such as fat cells and fibroblasts, as well as blood vessels and immune cells. All of these cells together with the cancer cells make the "tumor microenvironment." One specific cell type within the tumor microenvironment is mesenchymal stem cells (MSC). MSC are responsible for dividing into the supporting/stromal cells of the microenvironment. The different cells within the tumor microenvironment are all sending messages back and forth to each other, causing changes in each cell and ultimately causing the cancer to grow larger. Current chemotherapy treatments for women with ovarian cancer attack the cancer cells, but have little effect on the other cells in the microenvironment, which are still sending signals for the cancer cells to multiply. If we can also target the messages/signals between the cancer cells and the other microenvironment cell types, we can treat cancers more effectively. Successful new treatments such as this will ultimately allow women with ovarian cancer to live longer lives. Our laboratory previously isolated MSC from the tumors removed from women with ovarian cancer at the time of their surgery. These cancer-associated MSC (CA-MSC) send signals that are different than those made by MSC in women who do not have cancer. Two related signals, IL6 and LIF cytokines, are being sent at higher than normal levels from CA-MSC in women with ovarian cancer. These IL6 and LIF messages are received and processed in cancer cells using the same pathway. Treatments blocking IL6 signals are currently being tested in women with ovarian and other cancers. However, we worry that LIF messages from the CA-MSC will still activate the same pathway in the cancer cells to promote growth and therefore prevent IL6-blocking treatments from being effective. We believe that treatments against the shared pathway parts of IL6/LIF signals will be better for women with cancer. For example, there are treatments being used for blood cancers that target this shared pathway, such as the medicine ruxolitinib. Our research will study using these medicines to treat ovarian cancer. A second focus of our work is to determine if IL6/LIF messages from CA-MSC alter a cancer s response to hormonal therapy, including tamoxifen. Hormonal therapy can be an effective treatment for some women with ovarian cancer and has significantly fewer side effects than chemotherapy. It has been proposed that IL6 messages create resistance to tamoxifen. Therefore, we believe that blocking IL6/LIF messages from CA-MSC will improve responses to tamoxifen. The objectives of this study are (1) to determine whether blocking the shared pathway proteins of IL6/LIF messages from CA-MSC is better than just blocking IL6 messages, (2) to determine if blocking IL6/LIF messages improves our ability to kill ovarian cancer cells with tamoxifen, and (3) to determine how the IL6/LIF and hormonal messages are interacting within cancer cells. For all of these experiments, MSC will be grown together with cancer cells, either in tissue culture conditions or in mice, to model the tumor microenvironment. This research has clinical application in the development of new treatments for women with ovarian, primary peritoneal, or fallopian tube cancers, with the goal of helping these women live longer lives. The findings of this study also have the potential to help women and men with other cancer types. The time to a patient-related outcome from this research will depend on whether the identified signals have medicines that already exist and target those signals (such as ruxolitinib and tamoxifen). If such medicines exist, then early clinical trials are feasible in the next 3-10 years. If drug development and preclinical animal model testing are necessary, then clinical trials in patients will be attainable in 10-15 y
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510194
Entities
People
- Karen McLean
Organizations
- United States Army
- University of Michigan