Role of the CXCL5/CXCR2 Axis in Breast Cancer Metastasis to Bone and Initiation of Colonization

Doctoral Dissertation
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Abstract

Breast cancer is the most diagnosed cancer in women, affecting one in eight women in the United States, and is the leading cause of cancer related deaths, second only to lung cancer. Metastatic breast cancer tumors, rather than the primary tumors themselves, contribute to the patient’s death. The most common tissue for breast cancer to metastasize is bone. A major challenge in the study of breast cancer metastasis to bone is the lack of experimental models that target the last steps of the metastatic cascade in the context of the bone microenvironment. In this thesis, I developed a novel methodology to study breast cancer metastasis to the bone ex vivo. After validation of this model as a useful tool for cancer research, I used it to study the effects of paracrine signals sent by the bone, marrow, and cancer cells to promote bone colonization.

With our system, I identified multiple cytokines and chemokines as potential players in the progression of breast cancer metastasis to the bone including CXCL5, CXCL2, CXCL10, TNFa, and VEGF. Proteins associated with cancer initiation, growth, EMT, and metastasis.

I studied the effects of CXCL5 in our co-culture system of bone and cancer cells. CXCL5 is part of the ELR+ subfamily of chemokines and interacts with CXCR2, which is CXCL5’s only known functional receptor. I discovered that bone co-cultures of cancer cells with cancer-primed bone induce cancer colonization and secrete higher levels of CXCL5 into the culture media when compared to co-cultures using healthy bones. Moreover, addition of exogenous CXCL5 to co-cultures is sufficient to promote cancer cell proliferation and bone colonization in co-culture. Furthermore, blocking CXCR2 also reduces cancer cell proliferation and inhibits metastatic colonization of the bone.

This study provides a new experimental platform that will allow us to better understand what drives cancer to metastasize to bone and, thus, to develop better treatment options for patients with bone metastasis.

Attributes

Attribute NameValues
Author Ricardo Romero-Moreno
Contributor Sharon Stack, Committee Member
Contributor Glen Niebur, Committee Member
Contributor Laurie E. Littlepage, Research Director
Contributor Siyuan Zhang, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Integrated Biomedical Sciences
Degree Name Doctor of Philosophy
Banner Code
  • PHD-IBCH

Defense Date
  • 2019-06-24

Submission Date 2019-11-25
Subject
  • Bone bioreactor

  • Ex vivo culture

  • CXCL5

  • Bone metastasis

  • CXCR2

  • Breast cancer

Record Visibility Public
Content License
  • All rights reserved

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