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Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer.

ABSTRACT: Breast involution following pregnancy has been implicated in the high rates of metastasis observed in postpartum breast cancers; however, it is not clear how this remodeling process promotes metastasis. Here, we demonstrate that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. Moreover, lymphatic vessel density was increased in normal postpartum breast tissue compared with tissue from nulliparous women. In rodents, mammary lymphangiogenesis was upregulated during weaning-induced mammary gland involution. Furthermore, breast cancer cells exposed to the involuting mammary microenvironment acquired prolymphangiogenic properties that contributed to peritumor lymphatic expansion, tumor size, invasion, and distant metastases. Finally, in rodent models of postpartum breast cancer, cyclooxygenase-2 (COX-2) inhibition during the involution window decreased normal mammary gland lymphangiogenesis, mammary tumor-associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Our data indicate that physiologic COX-2-dependent lymphangiogenesis occurs in the postpartum mammary gland and suggest that tumors within this mammary microenvironment acquire enhanced prolymphangiogenic activity. Further, our results suggest that the prolymphangiogenic microenvironment of the postpartum mammary gland has potential as a target to inhibit metastasis and suggest that further study of the therapeutic efficacy of COX-2 inhibitors in postpartum breast cancer is warranted.

SUBMITTER: Lyons TR

PROVIDER: S-EPMC4153700 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Project description:Hematogenous metastasis requires tumor cells to detach from primary tumor into blood/lymphatic circulation and extravasate. Tumor cells in the blood circulation system, named circulating tumor cells (CTCs), are in a suspension state, with unique cytoskeletal structure and molecular phenotype different from primary tumor cells. The aim of this study is to assess the impact of suspension state on the metastatic potential of breast cancer cells (BCCs) and study its underlying mechanism. Methods: BCCs were cultured on low-adhesion plates to mimic the suspension state. Conventional adherent culture BCCs were used as the control. This study examined the metastatic potential of adherent and suspension BCCs in vitro and in vivo. RNA sequencing analysis, siRNA, and inhibitors were used to determine the underlying molecular mechanism. Results: The suspension state significantly increased the metastatic potential of BCCs, but slightly suppressed their tumor growth. RNA sequencing analysis revealed that the suspension state resulted in an acquisition of unique molecular signature enriched in pro-metastatic and tumor-suppressive genes. Specifically, prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes protein cyclooxygenase-2 (COX-2), was identified as a highly up-regulated gene in suspension state compared with adherent cultured BCCs. Inhibition of the catalytic activity of COX-2 by celecoxib markedly suppressed suspension-increased migration and invasion of BCCs. In addition, knock-down of COX-2 by siRNA reduced the experimental lung metastasis formation of suspension cultured BCCs, which was associated with a remarkable decrease in retention and survival of BCCs in lungs of mice in the early stage of metastasis. Activation of Ca2+/calcineurin (CaN)/nuclear factor of activated T cells (NFAT) pathway and disruption of cytoskeleton contributed to the COX-2 up-expression by suspension state. Conclusions: Our results demonstrate that suspension state plays an important role in the metastatic potential of CTCs, and suggest a potential application of COX-2 inhibitor for anti-metastasis.

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Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer.

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