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 (DTC) 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.

Figure 1.

Overview of the metastatic process and mechanisms regulating breast cancer dormancy. A, Schematic illustration summarizing the stations the cancer cells pass through before homing the secondary site. Different mechanisms can either induce and maintain the DTCs’ dormancy, mediate their survival during dormancy, or induce their outgrowth. B, In the bones, osteogenic niche induces the outgrowth, meanwhile, NG2+/Nestin+ MSCs inhibit it. C, In muscle, high oxidative stress impedes metastatic outgrowth, and overexpressing catalase counteracts this effect. D, In the liver, NK cells induce the DTCs’ quiescence, meanwhile, activated HSCs can alleviate this effect. In vitro work suggested that HSC-derived IL8 induces the DTCs’ proliferation. E, In the brain parenchyma, astrocytes and NK cells can keep the DTCs in dormancy. DTC-secreted lactate counteracts the NK effect. F, In the lungs, DTC-secreted COCO and inflammation-induced NETs enhance the DTCs’ outgrowth. Cross-talk between the lung cells (AT1/2) with DTCs upregulates SFRP2 in DTCs as a survival cue.

Figure 2.

Historical timeline for the landmark concepts and studies of breast cancer metastatic dormancy. Early studies complied evidence that cancer cells can form undetectable tumors in different settings, hence introducing the dormancy notion. The era of 1970s to the 2000s, witnessed establishing the metastatic inefficiency and angiogenic dormancy concepts. In parallel, key research models were generated and characterized. The following era (2000–2010) witnessed key insights about cellular dormancy (94, 95, 218) and metastasis in general such as the premetastatic niche. The last decade witnessed the integration between the tumor microenvironment and dormancy directions, with a clear exponential increase in studies revealing novel mechanisms involved in the dormancy dynamics (summarized in Fig. 1).