Physical activity has been consistently linked to decreased incidence of breast cancer and a substantial increase in the length of survival of patients with breast cancer. However, the understanding of how applied physical forces directly regulate breast cancer remains limited. We investigated the role of mechanical forces in altering the chemoresistance, proliferation and metastasis of breast cancer cells. We found that applied mechanical tension can dramatically alter gene expression in breast cancer cells, leading to decreased proliferation, increased resistance to chemotherapeutic treatment and enhanced adhesion to inflamed endothelial cells and collagen I under fluidic shear stress. A mechanistic analysis of the pathways involved in these effects supported a complex signaling network that included Abl1, Lck, Jak2 and PI3K to regulate pro-survival signaling and enhancement of adhesion under flow. Studies using mouse xenograft models demonstrated reduced proliferation of breast cancer cells with orthotopic implantation and increased metastasis to the skull when the cancer cells were treated with mechanical load. Using high throughput mechanobiological screens we identified pathways that could be targeted to reduce the effects of load on metastasis and found that the effects of mechanical load on bone colonization could be reduced through treatment with a PI3Kγ inhibitor.
Cancer metastasis, the spread of cancer cells to distant organs, is responsible for 90% of cancer‐related deaths. Cancer cells need to enter and exit circulation in order to form metastases, and the vasculature and endothelial cells are key regulators of this process. While vascularized 3D in vitro systems have been developed, few have been used to study cancer, and many lack key features of vessels that are necessary to study metastasis. This review focuses on current methods of vascularizing biomaterials for the study of cancer, and three main factors that regulate intravasation and extravasation: endothelial cell heterogeneity, hemodynamics, and the extracellular matrix of the perivascular niche.
more » « less- Award ID(s):
- 1454806
- NSF-PAR ID:
- 10457205
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Healthcare Materials
- Volume:
- 9
- Issue:
- 8
- ISSN:
- 2192-2640
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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