Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer

Abstract

Lymphangiogenesis (formation of new lymphatic vessels), unlike angiogenesis, has been a lesser-focused field in cancer biology, because of earlier controversy regarding whether lymphatic metastasis occurs via pre-existing or newly formed lymphatics. Recent evidence reveals that peri-tumoral or intra-tumoral lymphangiogenesis is a precursor for lymphatic metastasis in most carcinomas and melanomas. Two major lymphangiogenic factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, are produced by cancer cells or immune cells such as macrophages in the tumor-stroma to promote sprouting of lymphatics from lymphatic endothelial cells (LEC) or LEC precursors (LECP) by binding to their primary (high affinity) receptor VEGF-R3 or secondary receptors VEGF-R2, neuropilin (NRP)2 and α9/β1 integrin. Many other growth factors/receptors such as VEGF-A/VEGF-R2, fibroblast growth factor (FGF)2/FGF-R, platelet-derived growth factor (PDGF)/PDGF-R, hepatocyte growth factor (HGF)/C-Met, angiopoietins (Ang)1, 2/Tie2, and chemokines/ chemokine receptors (CCL21/CCR7, CCL12/CCR4) can also stimulate LEC sprouting directly or indirectly. This review deals with the roles of prostaglandins (PG), in particular PGE2, in cancer-associated lymphangiogenesis, with special emphasis on breast cancer. We show that cyclooxygenase (COX)-2 expression by breast cancer cells or tumor stroma leading to high PGE2 levels in the tumor milieu promotes lymphangiogenesis and lymphatic metastases, resulting from binding of PGE2 to PGE receptors (EP, in particular EP4) on multiple cell types: tumor cells, tumor-infiltrating immune cells, and LEC. EP4 activation on cancer cells and macrophages upregulated VEGF-C/D production to stimulate LEC sprouting. Furthermore, ligation of EP4 with PGE2 on cancer or host cells can initiate a new cascade of molecular events leading to cross-talk between cancer cells and LEC, facilitating lymphangiogenesis and lympho-vascular transport of cancer cells. We make a case for EP4 as a potential therapeutic target for breast cancer.

The Role of Cyclooxygenase-2 in Colorectal Cancer

“…As a result, physiological or pathological processes follow [23,42]. Recent investigations support that PGE 2 may enhance progression of colorectal cancer [41,43,44], and EP4 is a therapeutic target for cancer therapy [45,46]. COX-2 derived PGE 2 can also contribute to tumor development through several mechanisms including inhibition of apoptosis.…”

Neuropilins in the Context of Tumor Vasculature

“…The repertoire of NRP2 ligands within the VEGF family comprises VEGF-A 145 and VEGF-C. Upon binding its ligand, NRP2 forms a ternary complex with VEGF-C and VEGFR3 on lymphatic ECs and is involved in lymphangiogenesis [61,116].…”

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

“…This pathway is thought to be involved in alterations observed in lymphedematous tissues, such as fibrosis, adipose deposition, and lymphatic dysfunction (48,90). Interestingly, it has been recently observed that cyclooxygenase (COX)2 and its product prostaglandin (PG)E2 are overexpressed in breast cancer stroma, having a possible role in lymphangiogenesis and metastatic spread s through lymphatics (91). Specifically, PGE2 activates the EP4 receptor in cancer cells and macrophages, promoting local VEGF-C/D overexpression, and LECs proliferation (91).…”

“…Interestingly, it has been recently observed that cyclooxygenase (COX)2 and its product prostaglandin (PG)E2 are overexpressed in breast cancer stroma, having a possible role in lymphangiogenesis and metastatic spread s through lymphatics (91). Specifically, PGE2 activates the EP4 receptor in cancer cells and macrophages, promoting local VEGF-C/D overexpression, and LECs proliferation (91). All this information opens new avenues in BCRL risk stratification, providing that further prospective clinical studies will be designed to investigate whether NFKB2, IL10, IL4, and EP4 can be employed as circulating biomarkers for pre-surgical risk assessment.…”