PITTSBURGH — In most cases of breast cancer, no evidence of spread is found, the primary tumor is removed and the patient is as close to cured as possible, at that point. In 10% to 30% of cases in women, however, distant metastases recur after years to decades.
“This is due to breast cancer cells disseminating to distant organs and lying quiescent. This is called metastatic dormancy,” explained authors from the University of Pittsburgh, the Pittsburgh VA Healthcare System and Chinese colleagues. “Dormant cells are generally resistant to chemotherapy, hormone therapy and immunotherapy as they are non-cycling and receive survival signals from their microenvironment. In this state, they are clinically irrelevant. However, risk factors, including aging and inflammation, can awaken dormant cells and cause breast cancer recurrences, which may happen even more than ten years after the primary tumor removal.”
The study in the International Journal of Molecular Sciences pointed out that how these breast cancer cells remain in dormancy is being worked out, with a key element apparently being the mesenchymal stem cells in the bone marrow that have been shown to promote breast cancer metastatic dormancy in recent studies.1
The authors advised that Indirect co-culture, direct co-culture and exosome extraction were conducted to investigate the modes of signal operation. Multiple signaling molecules that act in this process include both protein factors and microRNAs, they add, pointing out that integration of the studies allowed them to summarize current findings and gaps in the field and suggest future research directions for this field.
Background information in the article noted that breast cancer is one of the most common cancers worldwide and the leading cause of cancer deaths in women. In recent years, breast cancer accounts for around 30% new female cancer cases and 15% of new deaths of female cancer in the United States, making it the most common cancer type with the second highest death toll for American women, the researchers wrote.
“Despite this high death toll, most breast cancers are caught early when there is no evidence of distant spread; these cancers are treated as localized diseases and removed. When these breast-limited cancers are removed, the 10-year survival rate exceeds 80%,” they add. “Yet, many of these seemingly ‘cured’ cancers recur as metastases in distant sites, leading to mortality years to decades later. Thus, understanding why the disseminated breast cancer cells (BCC) reactivate and grow into lethal tumors is critical to conquering this cancer.”
The study found that at least part of the tendency for recurrence is hardwired in the BCC themselves. “The cells that lead to these cancers express female sex hormone receptors for estrogen (ER) and progesterone (PR) and are responsive to these hormones; however, as some cancers develop, they become resistant to signaling from ER and PR,” the authors explained. “This is one of the major divides in breast cancer classification (in addition to the proposed cell of origin of the breast cancer), decided by the “positive or negative” state of ER, PR, as well as a tumor growth-promoting receptor called human epidermal growth factor receptor 2 (Her2).”
The report described how the distinction of ER expression not only determines treatment, with hormonal blockade being used against ER-positive tumors, but also prognosis. “For ER-negative patients, which account for 20–40% of all breast cancers,” the researchers wrote, “the distant recurrence usually occurs 3–5 years after primary tumor diagnosis; while for ER-positive patients, most breast cancer recurrence appears 5 years after the diagnosis and remains possible even 15 years later. Within 20 years following diagnosis, 13–41% of ER-positive patients with endocrine therapy for 5 years will experience tumor recurrence, mainly leading to deaths. Because of the possibility of recurrence, breast cancer is considered as an “incurable” disease.”
The authors suggested that future studies will need to delineate a clearer mechanism by which mesenchymal stem cells (MSCs) regulate breast cancer metastatic dormancy, adding, “More signal molecules, their correlations, and related signaling pathways are to be investigated. Depending on whether we find a signal that is sufficient to induce dormancy on its own, or those required to maintain dormancy will dictate which of these two therapeutic approaches will dominate.”
- Dai B, Clark AM, Wells A. Mesenchymal Stem Cell-Secreted Exosomes and Soluble Signals Regulate Breast Cancer Metastatic Dormancy: Current Progress and Future Outlook. Int J Mol Sci. 2024 Jun 28;25(13):7133. doi: 10.3390/ijms25137133. PMID: 39000239; PMCID: PMC11241820.
