Cellular dormancy in minimal residual disease following targeted therapy
| Autor: | Suzanne J. Bakewell, Susan E. Moody, Christopher J. Sterner, Rita Singh, Hans E. Seidel, Sanjeethan C. Baksh, Tien-chi Pan, Jason R. Ruth, George K. Belka, Dhruv K. Pant, Lewis A. Chodosh, Blaine A. Keister |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Epithelial-Mesenchymal Transition
Neoplasm Residual Receptor ErbB-2 medicine.medical_treatment Breast Neoplasms Mice Transgenic Stem cells Wnt1 Protein Biology Quiescence medicine.disease_cause Disease-Free Survival Targeted therapy 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Recurrence medicine Dormancy Animals Humans Molecular Targeted Therapy Neoplasm Metastasis RC254-282 030304 developmental biology 0303 health sciences Neovascularization Pathologic EMT Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cell cycle Residual disease medicine.disease Minimal residual disease Primary tumor 030220 oncology & carcinogenesis Cancer cell Cancer research Neoplastic Stem Cells Female Gene expression Stem cell Neoplasm Recurrence Local Carcinogenesis Research Article |
| Zdroj: | Breast Cancer Research : BCR Breast Cancer Research, Vol 23, Iss 1, Pp 1-23 (2021) |
| ISSN: | 1465-542X 1465-5411 |
| Popis: | Background Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. Methods To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. Results We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. Conclusions Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence. |
| Databáze: | OpenAIRE |
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