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Novel biomarkers for bone metastases – from mechanism to analytics and back

Subject Area Gynaecology and Obstetrics
Hematology, Oncology
Orthopaedics, Traumatology, Reconstructive Surgery
Term from 2020 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 432406196
 
Final Report Year 2024

Final Report Abstract

Bone metastases remain a significant challenge in the clinical management of patients with breast and prostate cancer and are associated with pain, immobility, diminished quality of life, and increased mortality rates. Recent conceptual advancements and research suggest that biologically active proteins regulating the cancer-bone dialogue have the potential to serve as biomarkers to predict the onset and/or progression and improve the outcome of patients with bone metastases. Preliminary investigations by the applicants have shown that the protein osteoprotegerin (OPG) is significantly linked to increased risk of death in patients with breast cancer. The objective of the project was to i) verify OPG as a prognostic marker in women with breast cancer and bone metastases and ii) to identify novel biomarkers in both breast cancer and bone metastases. In the initial phase of the project, OPG was either knocked down or overexpressed in vitro in human osteotropic breast and prostate cancer cell lines (MDA-MB-231, PC3). This manipulation had neither significant effects on vitality, migration, or apoptosis of the cells, nor on the regulation of inflammatory cytokines or chemokines associated with bone metastases. However, analyses utilizing a clinical cohort of patients with early breast cancer who received neoadjuvant systemic therapy revealed a significant association between elevated serum OPG levels and poorer prognosis, irrespective of the bone metastasis status. While the in vitro data conflicted with the initial hypothesis, these clinical data underscore the role of OPG in breast cancer necessitating further investigations. It is crucial to not only assess this role in the context of bone metastases but also concerning primary tumor growth and/or the presence of nonbone metastases. In the second part of the project, we successfully demonstrated the prognostic relevance of leucine-rich α-2 glycoprotein 1, periostin, and Neuropilin-1 in women with early breast cancer. Elevated serum levels of Neuropilin-1 and Dickkopf-1 (DKK-1) in patients with ovarian cancer were associated with reduced disease-free and overall survival rates and increased risk of recurrence. In addition, we were able to continue our research on the bone-related protein DKK-1. In consideration of the circumstances at that time, we examined DKK-1 levels in patients with COVID-19, identifying DKK-1 as a predictor of COVID- 19 mortilty. Moreover, we showed that DKK-1 controls inflammatory immune responses in tumor cells and immune cells in health and disease conditions. Collectively, the project confirmed the prognostic role of OPG as a biomarker in breast cancer, but could not confirm direct anti-tumor efficacy after OPG modulation. We identified novel tumor biomarkers and uncovered a novel role of DKK-1 in cancer and inflammation. Our findings have the potential to translate into potential future projects and hold promise for the development of new diagnostic and therapeutic strategies.

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