Bone Tropism of Breast Cancer Metastases: Dissecting the Role of Endothelial Adhesion Molecules through Human Organotypic Vascularized Microfluidic 3D Models
Abstract
This research project aims at understanding if the fact that breast cancer metastasizes to certain organs, such as bone, and not to others, such as skeletal muscle, can be due to the preferential interaction between breast cancer cells and the organ-specific endothelium. The metastasization process is constituted by several steps: Cells in the primary tumor become aggressive and start to migrate. They reach the blood vessels and survive in the blood flow, finally attaching to the endothelium of the target organs and invading them. They then start to proliferate into the organ itself, giving rise to secondary tumors. Metastasis is the primary cause of death for patients with cancer, accounting for 90% of cancer-related mortality; thus, our ability to reduce cancer related mortality is largely dependent on our capacity to interdict the metastatic process. In particular, up to 70% of advanced breast cancer patients present bone metastases and no therapy exists able to cure established bone metastases, so it is importance to stop the process before metastatic cells begin to proliferate. If this project is successful, we will be nearer to the elimination of bone metastases because we will have identified molecules that can be used as pharmacological targets to prevent breast cancer cells adhesion to the bone endothelium, thus impeding breast cancer cells migration through it. Up to now, studies on breast cancer derived bone metastases have been performed with animal models or with very simplified systems developed in research laboratories, which present, however, several limitations. Besides ethical issues related to animal studies, they do not represent adequately all the steps of the mechanisms that take place in the human organism and do not allow sophisticated analyses needed for the study of metastases. On the other hand, the simplified laboratory systems are usually bi-dimensional and based on rigid plastic supports, very different from the complexity of human native tissues. In recent years, novel advanced laboratory systems, called microfluidics chips, have been developed, which will help to perform experiments in conditions more similar to those present in the organism. Such devices can be used for the study of the metastatic process, since they can be constituted by human cells identical to those present in the tissues of the organ to which tumor metastasize. Furthermore, cells are maintained in a three-dimensional environment, created with biocompatible materials, usually gels, resembling the milieu in which cells are immersed in vivo. In this project, we will develop and use microfluidic chips based on human cells that also have a channel covered with the same cells present in the physiological blood vessels, endothelial cells, to study the behavior of breast cancer cells in contact with endothelial cells. Performing our study with such advanced models will allow us to provide tools for the development of better therapies as compared to those achieved with standard methods. Moreover, the developed microfluidic chip can be the basis for the development of personalized diagnostic devices, made from a patient s own cells. Those systems would be able to predict the individual risk to develop bone metastasis, involving biological materials (both cells for the creation of the tissue and tumor cells) coming from the patient itself, allowing one to set up preventive strategies for the patient with higher risk of developing bone metastases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510092
Entities
People
- Matteo Moretti
Organizations
- Galeazzi Orthopaedic Institute
- United States Army