Varney Michelle L, Singh Rakesh K
Department of Pathology and Microbiology, The University of Nebraska Medical Center, 985900 Nebraska Medical Center Omaha, NE 68198-5900.
Am J Cancer Res. 2015 Jan 15;5(2):616-28. eCollection 2015.
Lymphangiogenic factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGFC-D, and their receptor, VEGF receptor-3 (VEGFR3), play a pivotal role in the promotion of metastasis to regional lymph nodes. In the present study we explored the role of VEGF-C as an autocrine growth factor for breast cancer cells.
We examined the expression of VEGF-C and VEGFR3 in mammary tumor cells lines and examined whether blocking the VEGF-C-VEGFR3/Flt4 pathway using a VEGFR3 antagonist would inhibit proliferation of mammary tumor cells resulting in a decrease in tumor growth and metastasis.
We report expression of VEGF-C and its receptor VEGFR3 by mammary tumor cells, and their association with aggressiveness. Inhibition of VEGF-C-VEGFR3/Flt4 in mammary tumor cells decreased their proliferation and survival. Mammary tumor bearing mice treated with a VEGFR3 antagonist showed a significant decrease in tumor growth and the extent of spontaneous and experimental lung metastases.
These findings demonstrate the VEGF-C-VEGFR3/Flt4 autocrine signaling pathway regulates mammary tumor cell survival and proliferation and that neutralization of VEGFR3 signaling might lead to development of a novel therapeutic approach for malignant breast cancer.
淋巴管生成因子，如血管内皮生长因子-C（VEGF-C）和VEGFC-D及其受体血管内皮生长因子受体-3（VEGFR3），在促进肿瘤转移至区域淋巴结中起关键作用。在本研究中，我们探讨了VEGF-C作为乳腺癌细胞自分泌生长因子的作用。
我们检测了乳腺肿瘤细胞系中VEGF-C和VEGFR3的表达，并研究使用VEGFR3拮抗剂阻断VEGF-C-VEGFR3/Flt4信号通路是否会抑制乳腺肿瘤细胞的增殖，从而导致肿瘤生长和转移减少。
我们报道了乳腺肿瘤细胞表达VEGF-C及其受体VEGFR3，以及它们与侵袭性的关联。抑制乳腺肿瘤细胞中的VEGF-C-VEGFR3/Flt4会降低其增殖和存活率。用VEGFR3拮抗剂治疗的荷乳腺肿瘤小鼠的肿瘤生长以及自发性和实验性肺转移的程度均显著降低。
这些发现表明VEGF-C-VEGFR3/Flt4自分泌信号通路调节乳腺肿瘤细胞的存活和增殖，并且中和VEGFR3信号可能会导致开发出一种针对恶性乳腺癌的新型治疗方法。
