Investigation of the Biochemical and Mechanical Cues Influencing Breast Cancer Metastasis to Trabecular Bone

Doctoral Dissertation
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Abstract

Over 90% of cancer-related deaths are due to metastases rather than the primary tumor. Bone is the most common site for breast cancer metastasis, and more than 70% of patients who die of breast cancer have bone metastases. The five-year survival rate in breast cancer patients with bone metastases is only 20%. Thus, a deeper understanding of how the bone environment influences cancer metastasis would provide information on possible prevention or treatment of the disease.

The reasons why breast cancer cells metastasize or how they decide to home in one tissue versus another remain inconclusive. There are several factors that make bone a common site for metastasis. Bone is highly vascularized, and disseminating tumor cells likely travel through the marrow to the axial skeleton where they most commonly form metastases. Evidence suggests that tumor cells may be attracted to and interact with MSCs, adipocytes, and various immune cells in the marrow. In addition, the unique mechanical environment of bone, with gel-like marrow encapsulated in relatively rigid bone, has been hypothesized to play a role in supporting metastasis. As the skeleton is primarily a load-bearing tissue, resident bone and marrow cells are subjected to mechanical stimulation. Cancer cells residing in bone will similarly experience mechanical stimulation and interact with resident cells. Thus, it is essential to understand how cancer cells respond to mechanical cues.

This research examined biochemical and mechanical cues present in bone and marrow that influence breast cancer cell migration into trabecular bone and marrow, and investigated the roles of varying mechanical properties and loading regimes on metastatic progression. Breast cancer cells were found to migrate toward bone within 3-D hydrogels, and their 2-D migration toward bone increased when marrow was present. Leptin, TNFα, IL-1β, and IL-6 were all found to increase due to the presence of bone marrow and may serve as potential chemoattractants for the cancer cells.

It is impossible to understand why metastatic cancer cells home to the bone marrow, without considering the mechanical cues present in the marrow and the mechanobiological response of these cells. When shear stress was imparted to the marrow, bone formation was observed. In addition, marrow cells altered their gene and protein expression in response to shear stress, indicating that they participate in mechanotransduction. These results provide information on the mechanical environment present in bone marrow that will be experienced by metastatic cancer cells residing in the tissue.

Metastatic breast cancer cells were affected by their mechanical environment. When cancer cells were embedded in soft and stiff gelatin hydrogels and exposed to perfusion or compression in a bioreactor, both substrate stiffness and compression affected spheroid size and altered expression of proteins involved in cancer-bone crosstalk. Taken together, this work contributes to a better understanding of the environment that could be used to further study, model, and develop treatments for bone metastasis.

Attributes

Attribute NameValues
Author Kimberly J. Curtis
Contributor Laurie Littlepage, Committee Member
Contributor Laoise McNamara, Committee Member
Contributor Glen L. Niebur, Research Director
Contributor Donny Hanjaya-Putra, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Bioengineering
Degree Name Doctor of Philosophy
Banner Code
  • PHD-BIOA

Defense Date
  • 2019-08-23

Submission Date 2019-11-26
Record Visibility Public
Content License
  • All rights reserved

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