Regulation of Tumor Cell ANGPTL4 by Astrocyte-Secreted TGF-Beta2 in Triple-Negative Breast Cancer Brain Metastases
Abstract
Brain metastases, which predict the worst outcome in almost all tumor patients, occur in about 15% to 30% of breast cancer cases and are becoming more common because of improvements in controlling the systemic disease. Triple-negative breast cancer, in which the cancer cells lack receptors for estrogen and progesterone and do not overproduce a protein called HER2, accounts for about 15% to 25% of all breast cancers. Although physicians know that triple-negative breast cancer is much more likely to metastasize to the brain than all other types of breast cancer, the reasons are unclear, so no effective treatments have been developed. We want to address this knowledge gap by targeting triple-negative cells to prevent them forming brain tumors. To become a tumor in a distant organ, metastatic cells must interact with that organ?s microenvironment. In the brain?s microenvironment, a subtype of brain glial cells called reactive astrocytes home in on invading tumor cells, associate them with growing metastatic lesions, and secrete proteins that encourage the lesions to enlarge. When we cultured triple-negative breast cancer cells in the laboratory in medium in which astrocytes had grown, the cancer cells became more malignant tumors and more metastatic growth in the brain. At the same time, they dramatically increased their production of a protein called ANGPTL4. In another experiment, we found that one protein secreted by human astrocytes, TGF- 2, made cultured triple-negative breast cancer cells increase their production of ANGPTL4. Moreover, it seems that in the astrocyte culture medium, TGF- 2 and ANGPTL4 both made TNBC more like cancer stem cells with the capability to survival and activation in the brain microenvironment. These observations suggest that astrocytes secrete TGF- 2 to stimulate tumor cell producing more ANGPTL4 when they encounter triple-negative breast cancer cells, making brain cancer stem cell activation and thus tumor growth, as well as worsening the disease. Therefore, novel intervention strategies that could prevent this process might be an effective treatment for brain metastases in patients with triple-negative breast cancer. To explore this possibility, we want to determine exactly how the TGF- 2 secreted by astrocytes tells cancer cells to make ANGPTL4. We also want to find out how ANGPTL4 makes brain lesions enlarge. By addressing one of breast cancer?s most difficult challenges ? why some breast cancers become life-threatening by metastatic growth in the brain ? this study could potentially lead to new and more precise ways to diagnose and treat patients with breast cancer. The translational impact of this study is summarized below. Translational research using ANGPTL4 and associated signaling for brain metastases in triple-negative breast cancer? ? Monitoring the level of ANGPTL4 in plasma and cerebrospinal fluid of triple-negative breast cancer patients to predicate the risk and progression of brain metastases, as well as evaluate therapeutic efficacy. ? Target ANGPTL4 signaling to treat brain metastases in triple-negative breast cancer. ? Target TGF 2 signaling to treat brain metastases in triple-negative breast cancer. ? Combination therapy to target ANGPTL4 and TGF 2 signaling to treat brain metastases in triple-negative breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710360
Entities
People
- Ling Wang
Organizations
- Medical College of Wisconsin
- United States Army