Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

Abstract

Multiple factors act in concert to define the fate of disseminated tumor cells (DTCs) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.

Unveiling the role of cellular dormancy in cancer progression and recurrence

“…However, further evidence is required to substantiate this hypothesis. Interestingly, this notion aligns with prior work indicating that quiescence might be inevitable in disseminated cells, with bottleneck events lying rather in the subsequent reactivation of proliferation and the transition from micro- to macro-metastases [15 ▪ ].…”

“…It is also important to recognize that the induction of a dormant program is not an isolated, cell-autonomous process. In particular, the tumor microenvironment (TME), encompassing both stromal cells and extracellular matrix (ECM), plays a critical role in the establishment of metastatic dormancy [4,15 ▪ ]. Both intrinsic and extrinsic factors of the TME can sustain dormancy, such as TGF-β, WNT5a, several laminins and collagens [54 ▪ ,55 ▪ ,56 ▪ ,57,58 ▪ ].…”

“…Ongoing investigations have since expanded the concept beyond metastases and significantly enriched our comprehension of the underlying molecular mechanisms (Fig. 1) [3 ▪ ,15 ▪ ]. Dormant cells usually constitute a minor fraction of unchallenged parental tumors (<5%), but many cancer therapies promote their emergence [16–18].…”

Wounding the stroma: Docetaxel’s role in dormant breast cancer escape

“…Elucidating cellular mechanisms that underlie breast cancer recurrence following surgery, chemotherapeutics, and chronic inflammation is critical to improving therapeutic efficacy [ 1 ]. Despite the growing recognition of the tumour microenvironment’s (TME) role in awakening dormant cancer cells, details of cellular communication networks remain largely unresolved [ 2 ]. In a recent report in PLOS Biology , Ganesan and colleagues illuminate a hitherto unknown mechanism of breast cancer recurrence wherein the TME drives progression [ 3 ].…”

“…The TME drives cancer progression by promoting cancer stem cell self-renewal, plasticity, chemoresistance, and immunotolerance through autocrine and paracrine signalling networks [ 2 , 4 , 5 , 8 ]. Cellular (stromal, endothelial, immune cells) and noncellular components (extracellular vesicles, cytokines), along with extracellular matrix composition influence transitions into a dormant versus awakened cancer cell state.…”