Inflammatory lymphangiogenesis in postpartum breast tissue remodeling

Abstract

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 ...

Deciphering Pro-Lymphangiogenic Programs during Mammary Involution and Postpartum Breast Cancer

“…However, their analysis included only a single timepoint during involution, involution day 10, which is near the end of the involution process in mice. In contrast, while our results also reveal that the number of Lyve-1 positive vessels per area in rodent mammary glands similarly drops from pregnancy to lactation, we observe that this drop is accompanied by a subsequent rise in LVD during the early phases involution, which peaks at involution day 6 in mouse and at day 10 in rat mammary tissue (38, 41) (Figure 1B). These results suggest that neo-lymphangiogenesis occurs during the active phase of mammary remodeling in rodents.…”

“…During the second phase (days 3–14), a remodeling program is initiated which results in additional cell death, increased expression of matrix remodeling proteases, degradation and remodeling of extracellular matrix components, and re-differentiation of adipocytes. Recently, we observed that neo- lymphangiogenesis occurs during postpartum mammary gland involution; however, the functional significance of these increased lymphatics has yet to be described (38, 41). Prior to our studies only a few reports had focused on mammary lymphatics, which are described below.…”

“…Macrophages have also been shown to participate directly in lymphangiogenesis via inducing lymphatic vessel sprouting and incorporating into existing tumor-associated lymphatics (69, 80). COX-2 and its product PGE2 also promote lymphangiogenesis in the tumor microenvironment (38, 41, 98, 99, 101, 102, 116, 120, 121). Furthermore, VEGF-D promotes lymphatic vessel dilation through a COX-2-dependent mechanism.…”

“…Mechanisms underlying this aggressive tumor promotional phenotype of involution include the induction of immunosuppression and lymphangiogenesis in the tumor microenvironment. Focusing on lymphangiogenesis, involution appears to be a period of significant lymphatic growth and remodeling, and human postpartum breast cancers have high peritumor lymphatic vessel density (LVD) and increased incidence of lymph node metastasis (2, 38, 41). Thus, we believe lymphangiogensis is an important pathway in the metastasis of postpartum breast cancer.…”

Lymphatic endothelial cells prime naïve CD8+ T cells into memory cells under steady-state conditions

“…However, in the setting of chronic inflammation rich in inflammatory cytokines and danger signals, re-stimulation of LEC-educated cells would likely favor generation of cytotoxic effector T cells. Indeed, while controversial, lymphangiogenesis has been frequently associated with aggravation of inflammatory diseases and transplant rejection 66,67 .…”