Abstract
Simple SummaryCancer becomes lethal when it metastasizes to secondary sites, and for breast cancer metastasis to the liver is a serious clinical problem. Liver metastasis is promoted, in part, by changes to the liver environment, resulting in the formation of a metastatic niche that supports circulating tumor cells. Understanding how the liver niche support breast cancer cells may lead to development of treatments for patients with metastatic breast cancer. Here, we report that the developmentally regulated process of weaning-induced liver involution increases liver metastasis in cancer cells with otherwise low metastatic potential. Increased metastasis associates with unique immunological properties in the involuting liver, including reduced ability to activate T cells required for tumor cell clearance. These data establish physiologic liver involution as a model to understand the liver metastatic niche and suggest future research into whether the immune milieu identified in the involuting liver could be targeted to treat metastases more generally.In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.
Highlights
Breast cancer deaths are almost exclusively due to spread of the cancer to distant organs, i.e., metastasis, and young women with breast cancer are at a higher risk of dying from metastasis than older women [1,2]
To model the clinical observation that young women with good prognostic breast cancers can progress to metastatic liver disease [20], we used a syngeneic BALB/c mouse model where mammary tumor cells of low metastatic ability, D2.OR cells [21,22], are delivered directly to the liver via the portal vein [23]
A diagnosis of breast cancer within five years of a recent pregnancy is an independent predictor of liver metastasis, which suggests that the postpartum liver may be uniquely susceptible to metastasis as we demonstrate in the rodent models [18]
Summary
Breast cancer deaths are almost exclusively due to spread of the cancer to distant organs, i.e., metastasis, and young women with breast cancer are at a higher risk of dying from metastasis than older women [1,2]. The dominant paradigm to explain the increased deaths in younger women is that their tumors have intrinsic properties that increase metastatic capability In support of this hypothesis, young women are at increased risk of being diagnosed with poor prognostic HER2+ and triple negative (ER-PR-HER2-) breast cancers [2,3]. Research shows that young breast cancer patients have worse outcomes compared to older peers regardless of cancer subtype [4]. This suggests that tumor extrinsic factors, such as the microenvironment at the secondary site, might contribute to increased metastasis observed in young women. Efforts to investigate secondary environments permissive of metastatic growth have gained momentum as an approach to better understand and target metastasis [5,6,7,8]
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