Characterization of Clustered CTCs to Eliminate Breast Cancer Metastasis
Abstract
Distant spread or metastasis of breast cancer cells makes the disease systemic, often therapy-resistant. Metastasis is currently incurable and causing 90% of breast cancer deaths. Better understandings of these processes to develop innovative treatment approaches are needed. The occurrence of metastasis has many sequential steps: cancer cell migration away from the breast tissue, entering into blood vessels, traveling in the circulation (circulating tumor cells), and arriving to distant organs for implantation and new tumor growth. The success rate of individual circulating tumor cells (CTCs) to create secondary tumors is extremely low. However, recent studies report that if more than two CTCs travel together as clusters, they have 50 times higher likelihood of regenerating tumors in distant organs is than individual CTCs. More importantly, the existence of CTC clusters predicts poor outcomes of breast cancer patients. The key question is what features of cancer cells allow them to cluster together and travel in the blood circulation to promote their implantation in other organs? Better understanding of these processes will engender the development of more targeted prevention methods and elimination of clustered CTCs for better outcomes of treatment of breast cancer. Our pilot studies indicate that CTCs with stem cell properties, cancer stem cells (CSCs), are capable of forming clusters. We hypothesize that CSCs mediate CTC cluster formation and distant metastasis. Compared to other cancer cells, these clustered cells survive better in the circulation and mediate more efficient metastases into the lungs, likely with assistance of platelets, small cell fragments without nucleus that participate in hemostasis. We aim to (1) characterize the interaction pathways among CSC markers/regulators and platelets, and (2) examine how CSC inhibition disrupts or blocks CTC cluster formation. Strategically, the investigators of the breast cancer group at the Case Comprehensive Cancer Center and the team members of this proposal have a large number of deposited clinical tumor/blood specimens from breast cancer patients for study. The investigative team of this proposal has established patient tumor-derived "mouse avatar" models. These models closely represent human metastatic disease of breast cancer. They follow the sequential steps of metastasis to other organs, thus providing an in vivo model system to dissect out these mechanisms and serve as a platform to develop new therapies. Our bench-bedside research team is composed of a basic scientist with expertise in breast CSCs and CTCs, a hematologist physician scientist with expertise in vascular biology, hemostasis, and platelets, an immunologist physician scientist with imaging expertise, a molecular epidemiologist and biostatistician with access to clinical blood samples, as well as junior investigator participants in the various laboratories. This proposal should: (1) greatly improve our understanding of CTCs and their role in metastasis in human breast cancer and representative models, (2) immediately accelerate the development of new diagnostic and prognostic biomarkers (e.g., detection of CTC or circulating CSC), and (3) broadly increase the development of innovative therapeutic approaches to target CTCs to reduce or eliminate metastasis associated breast cancer, the major cause of failure to cure breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610022
Entities
People
- Alvin Schmaier
Organizations
- Case Western Reserve University
- United States Army