Tumor-induced lymphangiogenesis in cervical lymph nodes in oral melanoma-bearing mice

Abstract

BackgroundMetastasis via the lymphatic system is promoted by lymphangiogenesis. Alterations of the lymphatic channels during the progression of metastasis to regional lymph nodes (LNs) remain unexplored. To examine whether tumor-induced LN lymphangiogenesis controls metastasis to regional LNs, we investigated cervical LN metastasis in a mouse model of oral melanoma.MethodsInjection of B16F10 melanoma cells into mouse tongues replicated spontaneous cervical LN metastasis. We performed histological, immunofluorescent, and histomorphometric analyses of tumor-reactive lymphadenopathy and lymphangiogenesis in tumor-associated LNs. We investigated the expression of vascular endothelial growth factor (VEGF)-C and its receptor, VEGF receptor-3 (VEGFR-3), in tumor cells and tissues, and LNs by reverse transcription polymerase chain reaction and immunofluorescence.ResultsTumor-associated LNs comprised sentinel LNs (SLNs) before and after tumor cell invasion (tumor-bearing SLNs), and LNs adjacent or contralateral to tumor-bearing SLNs. Extensive lymphangiogenesis appeared in SLNs before evidence of metastasis. After metastasis was established in SLNs, both LNs adjacent and contralateral to tumor-bearing SLNs demonstrated lymphangiogenesis. Interaction between VEGF-C-positive melanoma cells and VEGFR-3-positive lymphatic vessels was evident in tumor-associated LNs.ConclusionsLN lymphangiogenesis contributes a progression of tumor metastasis from SLNs to other regional LNs.

A specific immune and lymphatic profile characterizes the pre-metastatic state of the sentinel lymph node in patients with early cervical cancer

“…[3][4][5][6][7][8][9][10][11][12][13][14] The original spatial distribution analysis used in the present study additionally highlighted that main lymphatic vascular modulations occur in the subcapsular sinus, the Figure 3. Association between the lymphatic vessel density (D2-40) and densities of CD8 C T lymphocytes, Foxp3 C T lymphocytes, CD20 C B lymphocytes and PD-1 C germinal centers in DLN¡ and SLN¡.…”

“…Previous experimental studies in animal models have highlighted a lymphovacular remodeling (lymphangiogenesis) in the first draining LN (sentinel LN or SLN) that occurs prior to metastasis. [3][4][5][6][7][8][9] So far, only a few clinical studies have documented pre-metastatic lymphovascular process in the SLN of patients with lung, breast and oral squamous carcinomas. [10][11][12][13][14] Moreover, the mechanisms underlying the pre-metastatic regulation remain unknown and its relationship with inflammation and immune responses is not documented.…”

Structural alterations in tumor‐draining lymph nodes before papillary thyroid carcinoma metastasis

“…In the past, lymph node metastasis has been thought of as a relatively passive process, in which detached tumor cells drain via preexisting lymphatic vasculature to locoregional lymph nodes. 24,25 However, recent studies have demonstrated that tumor dissemination is a highly regulated process that is mediated by a complex array of molecular signals. 26,27 For example, vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor D (VEGF-D), which bind to and stimulate vascular endothelial growth factor 3 (VEGF-3) expressed on the lymphatic endothelium, are potent inducers of lymphatic endothelial proliferation and vessel enlargement.…”

3-O-Acetyloleanolic acid inhibits VEGF-A-induced lymphangiogenesis and lymph node metastasis in an oral cancer sentinel lymph node animal model

“…Changes in LNs begin before metastasis in a process termed tumor-reactive lymphadenopathy. Regional lymph nodes proximate to primary tumors are generally enlarged due to reactive lymphadenopathy, tumor metastasis, or both, suggesting that lymph nodes alteration results from interactions between the lymphatic system and tumors [ 5 , 6 ].…”