Growth factor signaling in the breast tumor microenvironment
Author
Summary, in English
In the papers included in this thesis, we made use of experimental breast cancer models to deepen our understanding of the tumor milieu and its clinical implications. Paper I reports the results of the preclinical trials of a compound that was designed to block activin receptor-like kinase (ALK)1, a protein involved in the formation of the blood vessels. Experimental models showed promising inhibition of tumor growth and marked reduction of the metastatic disease. In paper II, we analyzed how ALK1 communicates in different tumors in order to determine a set of characteristics that might help to predict which patients could benefit from ALK1-blocking therapy. Moreover, we discovered that the presence of ALK1 in tumor blood vessels influences the presence and function of the immune cells. In paper III, we define a novel therapeutic opportunity for the basal subtype of breast cancer, for which only surgery, radio- and chemotherapy are currently available. We identified the specific role of PDGF-C, that is released by tumor cells to activate fibroblasts. This communication loop maintains the tumor cells in a more aggressive state and makes them resistant to treatment. Thus, by blocking PDGF-C, tumor cells transform to a less aggressive luminal type and become sensitive to endocrine therapy, which can be used to limit the development of the tumor mass. Finally, paper IV gives us information about the diversity of the cells within the fibroblast population. By using a state of the art technology, we increased the resolution at which we are able to distinguish the function of each individual fibroblast isolated from a tissue, and match it with a specific cell-of-origin.
Taken together, the use of mouse models of cancer allows us to reproduce the complexity of human tumors, and delineate how these cellular relationships are shaped and maintained during tumor development. Our data illustrate the value of impinging on the crosstalk between tumor cells and other components of the tumor mass to develop novel therapeutic strategies for the clinical management of breast cancer.
Department/s
- Division of Translational Cancer Research
- Experimental oncology
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2018
Language
English
Publication/Series
Lund University, Faculty of Medicine Doctoral Dissertation Series
Volume
2018
Issue
129
Full text
Document type
Dissertation
Publisher
Lund University: Faculty of Medicine
Topic
- Cancer and Oncology
Keywords
- Breast cancer
- Tumor microenvironment
- Angiogenesis
- Cancer-associated fibroblasts
- PDGF-C
- ALK1
Status
Published
Research group
- Experimental oncology
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-697-7
Defence date
16 November 2018
Defence time
09:30
Defence place
Hörsalen Medicon Village, Scheleevägen 2, Byggnad 302, Lund
Opponent
- Morag Park (professor)