Tumor-derived VEGF-C, but not VEGF-D, promotes sentinel lymph node lymphangiogenesis prior to metastasis in breast cancer patients

Abstract

Breast cancer usually initially metastases to the sentinel lymph nodes (SLNs). Recent studies have demonstrated that tumor cells induce SLN lymphangiogenesis before metastasis in several malignancies. In addition, tumor-derived VEGF-C or VEGF-D may induce lymphangiogenesis and promote lymph node metastasis. To explore the mechanisms of lymph node metastasis in breast cancer, we investigated whether primary tumors induce SLN lymphangiogenesis before metastasis and determined the function of tumor-derived VEGF-C and VEGF-D in SLN lymphangiogenesis. Expression of VEGF-C and VEGF-D was examined using immunohistochemistry in 63 primary breast tumors. No significant relationships between VEGF-C and VEGF-D (P=0.420), and VEGF-C or VEGF-D expression and clinical parameters (age, tumor size, grade, hormonal receptor status, her-2 status) were observed (P>0.05). Expression of the lymphatic-specific markers VEGFR-3, Prox-1 and LYVE-1 was measured using quantitative real-time RT-PCR in uninvolved SLNs from 63 patients and compared to control lymph nodes from patients with benign breast disease. Expression of Prox-1 and LYVE-1 mRNA was significantly higher in uninvolved SLNs from breast cancer patients than that in control lymph nodes (P<0.01). Interestingly, expression of VEGFR-3, Prox-1 and LYVE-1 was significantly higher in SLNs from patients with high VEGF-C-expressing tumors than low VEGF-C-expressing tumors (P<0.05), but not VEGF-D-high-expressing tumors (P>0.05). This study demonstrates that primary breast tumors induce SLN lymphangiogenesis before metastasis occurs and that tumor-derived VEGF-C, but not VEGF-D, plays an important role in SLN lymphangiogenesis in breast cancer.

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¡.…”

“…[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 non-canonical role of vascular endothelial growth factor-C axis in cancer progression

“…[11][12][13] Enhanced expression of VEGF-C is prevalent in lymph node positive tumors and is associated with high lymphatic vessel density and poor survival such as in breast, prostate, and colon cancer. [14][15][16][17][18][19] The originally identified function of VEGF-C in cancer is similar to what has been observed in embryonic development as overexpression of VEGF-C in tumor cells induced peritumoral and intratumoral lymphangiogenesis in mouse models of breast cancer. 20 , 21 It is evident that increased tumor-associated lymphangiogenesis is sufficient to promote metastasis to regional lymph nodes and to distant organs.…”

Joint detection of multiple immunohistochemical indices and clinical significance in breast cancer

“…Thus far, VEGF is known as the most important angiogenesis-promoting factor, is highly expressed in several malignant tumors and plays an important role in the occurrence, development and metastasis of tumors (18,19). Combining VEGF with p53 status may result in a better prognostic prediction in BC patients (20).…”