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

Lyons, Traci R.; Borges, Virginia F.; Betts, Courtney B.; Guo, Qiuchen; Kapoor, Puja; Martinson, Holly A.; Jindal, Sonali; Schedin, Pepper

doi:10.1172/jci73777

Cited by 114 publications

(177 citation statements)

References 55 publications

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“…In this issue, Lyons et al take this notion one step further and demonstrate that lymphangiogenesis accompanies the tissue remodeling that occurs during postpartum mammary duct involution, a process that requires PGE 2 (10). Because lymphangiogenesis is part of the inflammatory remodeling program, the results of Lyons and colleagues suggest that pharmacological inhibition of PGE 2 signaling during the involution period could potentially help prevent postpartum metastatic breast cancer by inhibiting lymphangiogenesis.…”

Section: Lactation Involution and Breast Cancermentioning

confidence: 99%

“…The diversity of identified EP receptors is not surprising given the host of cell types in the tumor microenvironment (including tumor cells themselves) that can express prostaglandin receptors as well as secrete VEGF-C and VEGF-D. For example, in human lung and breast cancer cell lines, COX-2 overexpression has been shown to stimulate endogenous PGE 2 -mediated EP1 and EP4 signaling to drive upregulation of VEGF-C and VEGF-D directly by the tumor cells (7,9). In this issue, Lyons et al report that expression of PGE 2 by postpartum tumor cells stimulates LECs directly in an EP2-dependent manner (10), although other studies of tumor-associated stroma implicate EP3 (11,12). In human prostate cancer, EP3 protein levels were positively correlated with lymphatic vessel density (11), and COX-2-overexpressing Lewis lung carcinomas drove stromal cell secretion of VEGF-C via EP3 activation (12).…”

Section: Lactation Involution and Breast Cancermentioning

confidence: 99%

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Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Swartz

2014

J. Clin. Invest.

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C o m m e n t a r y3 7 0 Lymphangiogenesis in cancer, inflammation, and tissue remodelingLymphatic vessels are common routes for tumor cell metastasis, and sentinel lymph node metastasis is a major prognostic indicator of breast cancer outcome. Since the identification of lymphatic-specific growth factors VEGF-C and VEGF-D and their receptor VEGFR-3, numerous studies have demonstrated striking correlations between tumor-associated lymphangiogenesis, or peritumoral lymphatic expansion, and metastasis (1). Originally the correlation between lymphangiogenesis and tumor metastasis was attributed to increased accessibility for tumor cell dissemination, but recent studies have shown that tumor-associated lymphangiogenesis provides many immune-suppressive features to the tumor microenvironment and can pacify tumor-specific cytotoxic T lymphocytes as well as drive deletional tolerance of naive T cells (2, 3). On the other hand, lymphangiogenesis is not specific to the tumor microenvironment and generally accompanies all types of inflammation, particularly in late or chronic stages, including chronic infections, wound healing and tissue remodeling, autoimmune diseases like Crohn's disease, and the resolution phase of acute inflammation (3, 4). Lymphangiogenesis is driven by a host of inflammatory cells that secrete VEGF-C, including mast cells, neutrophils, macrophages, activated stromal cells, angiogenic blood endothelium, and B cells (3). These cells can upregulate their production of VEGF-C or VEGF-D upon exposure to prostaglandin E2 (PGE 2 ), which plays many important and complex roles in the tumor microenvironment.Overall, cyclooxygenase-2-driven (COX-2-driven) PGE 2 upregulation is thought to help control cytotoxic immune responses in later stages of inflammation; as such, it is also expressed in chronic infection and autoimmunity (5). The major actions of COX-2-dependent PGE 2 expression on leukocytes and stromal cells tend to be suppressive, and in the tumor microenvironment, this pathway drives development of myeloid-derived suppressor cells, regulatory T cells, and alternatively activated macrophages. In dendritic cells, PGE 2 upregulates suppressive factors, like IL-10 and indoleamine 2,3-dioxygenase (IDO), leading to dysfunctional T cell activation. Therefore, since these inflammatory events in the tumor microenvironment are coincident with lymphangiogenesis, teasing out the mechanisms by which lymphangiogenesis specifically contributes to cancer metastasis is inherently difficult. Function and consequences of inflammatory lymphangiogenesisDuring inflammation, lymphangiogenesis often involves hyperplasia of preexisting lymphatic vessels, increased vessel diameters, and decreased organization and patterning. The expanded lymphatic network in inflamed tissues often resembles the vascular plexus of the liver sinusoids or bone marrow vasculature. It remains controversial whether these altered vessels have increased transport functionsdraining fluid or carrying cells to the lymph node -but several recent studies ...

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Section: Lactation Involution and Breast Cancermentioning

confidence: 99%

Section: Lactation Involution and Breast Cancermentioning

confidence: 99%

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Swartz

2014

J. Clin. Invest.

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“…Rather, data implicate a unique biology of the postpartum breast in the promotion of postpartum breast cancer. Specifically, weaning-induced mammary gland involution is implicated because, in rodents, the tissue microenvironment of the involuting mammary gland enhances tumor growth, local tumor cell dissemination, and distant metastasis (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…Involution can be separated broadly into an initial phase of secretory epithelial cell death followed by a stromal remodeling phase that reestablishes the adipocytes and connective tissue as dominant constituents of the nonlactating gland (8,14). The stromal remodeling phase of involution shares numerous attributes with wound healing (15)(16)(17), including lymphangiogenesis (6), orchestrated immune cell infiltration, immune suppression (7,12), and deposition of a fibrotic-like extracellular matrix (ECM), mainly the fibrillar collagens (9,12). The mechanistic links between wound healing and cancer (18,19) and the known role of fibroblasts in these processes (20)(21)(22)(23) identify the mammary fibroblast as a potential mediator of postpartum breast cancer progression.…”

Section: Introductionmentioning

confidence: 99%

“…Intravital imaging studies provide additional support for collagen mediating tumor cell dissemination, as tumor cells migrate on mammary collagen fibers to gain access to vasculature (30,31). We have reported that targeting the window of postpartum involution with nonsteroidal antiinflammatory agents (NSAIDs) reduces the levels of the COX2 enzymatic product PGE2 during mammary gland involution (32) and is sufficient to reduce mammary tumor growth and metastasis to levels observed in nulliparous mice (5,6). The tested NSAIDs in those studies include COX2-nonspecific inhibitors ibuprofen and aspirin and the COX2-specific inhibitor celecoxib.…”

Section: Introductionmentioning

confidence: 99%

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Physiologically activated mammary fibroblasts promote postpartum mammary cancer

Guo¹,

Minnier²,

Burchard³

et al. 2017

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Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk

et al. 2019

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Key Points Question Is there an increased risk for metastasis of breast cancers that are diagnosed in young women post partum that extends beyond 5 years from the last childbirth, and what association do standard clinical prognostic factors have with metastatic risk in these young women when categorized by parity? Findings In a cohort study of 701 women 45 years or younger with breast cancer, those with stage I or II cancer diagnosed up to 10 years post partum had an increased risk for distant metastasis, with both estrogen receptor–positive and estrogen receptor–negative disease significantly affected. Meaning Postpartum status may be a prognostic indicator in young women with breast cancer and should be routinely identified, as up to 45% of women 45 years or younger with breast cancer fall into this category and could be at increased risk for metastasis.

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

Cited by 114 publications

References 55 publications

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk

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