Nodal Lymphangiogenesis and Metastasis

Abstract

Nodal lymphangiogenesis promotes distant lymph node (LN) metastasis in experimental cancer models. However, the role of nodal lymphangiogenesis in distant metastasis and in the overall survival of cancer patients remains unknown. Therefore, we investigated mechanisms that might facilitate regional and distant LN metastasis in extramammary Paget's disease (EMPD). We retrospectively analyzed the impact of tumor-induced lymphatic vessel activation on the survival of 116 patients, the largest cohort with EMPD studied to date. Nodal lymphangiogenesis was significantly increased in metastatic, compared with tumor-free, LNs (P ‫؍‬ 0.022). Increased lymphatic invasion within regional LNs was significantly associated with distant metastasis in LN (P ‫؍‬ 0.047) and organs (P ‫؍‬ 0.003). Thus, invasion within regional LNs is a powerful indicator of systemic tumor spread and reduced patient survival in EMPD (P ‫؍‬ 0.0004). Lymphatic vessels associated with tumors expressed stromal cell-derived factor-1 (SDF-1), whereas CXCR4 was expressed on invasive The metastatic spread of cancer cells from a primary site generally occurs in sentinel lymph nodes (LNs). Thus, the presence and extent of LN metastasis determines staging and prognosis in most human malignancies and often guides therapeutic decisions.1 Although surgical resection of primary tumors and their regional LN metastases can cure several types of cancer, distant LN and organ metastases represent a significant therapeutic concern due to the absence of effective antimetastatic therapies.

Metastatic Extramammary Paget’s Disease: Pathogenesis and Novel Therapeutic Approach

“…Recently, some studies have identified that the protein expression of molecules involved in proliferation and survival, including HER2 and mTOR, in the Paget cell (tumor cell of EMPD) is associated with invasiveness, metastasis, and OS ( 15 – 17 ). Similarly, translational research studies have demonstrated that cytokines, chemokines, and immune cells in EMPD confer favorable microenvironment for Paget cells to invade, migrate, and proliferate, thereby promoting metastasis ( 18 – 21 ). The results of current study support that the involvement of both Paget cells and tumor microenvironment factors is essential for metastasis; thus, the understanding of both aspects provides opportunities for the treatment of metastatic EMPD.…”

“…The clinical manifestation of erythematous, eczematous plaque of EMPD indicates the presence of vasodilation and hyperemia in the dermis of EMPD lesion. In fact, the histology of in situ and invasive EMPD lesions demonstrates a prominent enlargement and formation of several lymphatic and blood vessels in the dermis compared to those of healthy skin or other skin cancers such as melanoma ( 18 ). The immunohistochemical analysis established the expression of VEGF-A in Paget cells, as well as macrophages, and VEGF-C was also expressed in Paget cells ( 18 ).…”

Imaging tumor-induced sentinel lymph node lymphangiogenesis with LyP-1 peptide

“…Moreover, lymphangiogenesis requires lymphatic endothelial cell (LEC) differentiation to form mature lymphatic networks, and this complicated process is regulated by multiple growth factors, cytokines and chemokines (Ji 2009). Previous studies have demonstrated that lymphangiogenesis in the LNs in the postnatal period is considered to be a major contributor to tumor metastasis (Hirakawa et al 2009; Ji 2006). Since sentinel LNs are the first destinations in the spreading of cancer in many malignancies, lymphangiogenesis in the sentinel LNs may actively promote lymphatic metastasis.…”

The lymphatic system and pancreatic cancer

“…This expression pattern positively correlated with increased LVD values in the pancreas, lymph node metastasis frequency, and poor disease prognosis. Tumor-associated, but not normal uninflamed, LECs secrete ample amounts of CXCL12 in the tumor microenvironment and attract CXCR4 + tumor cells to lymphatic vessels and lymph nodes [208,209]. Blocking the CXCR4-CXCL12 signaling axis has resulted in impaired lymph node metastasis in numerous tumor models [210–212].…”