Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator

Abstract

Research on tumor-induced lymphangiogenesis has predominantly focused on alterations and abnormal growth of peritumoral and intratumoral lymphatic vessels. However, recent evidence indicates that lymphangiogenesis of sentinel lymph nodes might also contribute to cancer progression. In clinical oncology, the sentinel lymph nodes play an important role in diagnosis, staging and management of disease. The prognostic value that may be placed in the analysis of various parameters in tumor-free lymph nodes is still under debate. We, therefore, chose to investigate genetically fluorescent MDA-MB-435/green fluorescent protein human cancer cells transfected to overexpress VEGF-C in a nude mouse model and investigated metastasis, lymph node lymphangiogenesis, lymph node angiogenesis and size of sentinel lymph nodes. The nature of MDA-MB-435, identified as a breast cancer cell line for several decades, has recently been reidentified as being from melanoma origin. Vascular endothelial growth factor-C overexpression induced early metastasis and significantly increased the lymphatic vessel area in sentinel lymph nodes even before the tumor metastasis. At early time-points, expansion of the lymphatic network was observed even though no difference of blood vessel area and lymph node size was detected. These results suggest that primary tumors -via secretion of VEGF-C- can induce hyperplasia of the sentinel lymph node lymphatic vessel network and thereby promote their further spread. In cases of tumor-free lymph nodes the increased lymphatic network of sentinel lymph nodes is a very early premetastatic sign and may provide a new prognostic indicator and target for aggressive diseases.

Vascular Endothelial Growth Factor C Disrupts the Endothelial Lymphatic Barrier to Promote Colorectal Cancer Invasion

“…In contrast, upon systemic VEGFC delivery, metastasis is fostered in association with active lymphangiogenesis. Consistent with other findings, in the tumoral context we do not observe any effects on blood vessel density and enlargement upon VEGFC treatment 29,30 or VEGFR3 inhibition 7 . It is worthy of note that these experiments do not It is still unclear whether tumor cell intravasation/extravasation requires the transmigration of cancer cells through the cytoplasm of endothelial cells, as occurs for leukocytes, or whether they transmigrate between two adjacent endothelial cells after the disruption of cell-cell connections 19 .…”

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.…”

The lymphatic vasculature revisited

“…Despite the obvious clinical importance of tumor cell invasion into lymphatic vessels and colonization of the lymph nodes, current knowledge relies primarily on correlative studies. Mechanistic insights are only just beginning to emerge and comprise a better understanding of functions of the tumor microenvironment (32), the biochemistry of tumor cell invasion into lymphatics (33), and the transformation of the lymph node sinus into labyrinths that are lined by lymphatic endothelial-like cells (34), as reviewed in this series by Sinem Karaman and Michael Detmar (35). The knowledge in this field is not yet sufficiently developed to design targeted therapies against tumor spreading.…”