Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors

Abstract

Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4+ T-cells and an increase of cytotoxic CD8+ T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis.

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

“…COX-2 [47,48] WNT5B [49] WNT-1 inducible signaling pathway protein-1 [50] Prox-1 [51] FOXC2 [51] VEGF-D [52] Neuropilin 1 receptor [53] IL-6 [54] VEGF-C [47,[54][55][56] Periostin [55] ID-1 [57] A C C E P T E D M A N U S C R I P T Α-smooth muscle actin protein [58] NF-κB [56] Notch1 [56] Cancer-associated fibroblasts [ Table 1. A list of the markers discussed in section 2.2.…”

“…Honkanen et al hypothesized that VEGF-D may have different effects based on tumor stage, and they studied this phenomenon in squamous cell carcinoma. In early stage skin tumors, VEGF-D decreased type 2 T helper cell (Th2) response and increased m1/Th1 and Th17 polarization [52]. This decreases inflammation, promotes an environment that is anti-tumor, and allows for some tumor regression.…”

“…This decreases inflammation, promotes an environment that is anti-tumor, and allows for some tumor regression. However, in later stages of cancer, VEGF-D enables lymphangiogenesis and increases risk of metastases [52].…”

β‐Elemene inhibits 7,12‐dimethylbenz(a)anthracene/12‐O‐tetradecanoylphorbol‐13‐acetate‐induced skin tumorigenesis through suppression of NF‐κB‐associated signaling events in the mouse skin model

“…which accelerated to promote the mutated epithelial cells proliferation, which leads to skin tumor malignancy. [40] In our study, T A B L E 1 The levels of TBARS and antioxidants in skin tissues of control and experimental animals in each group [41] reported that antioxidants rich agents of protandim effectively suppresses the tumor growth and histological changes in chemically-induced skin cancer experimental model.…”

Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges

“…These results suggest that VEGF-D is dispensable for lymphatic development or the presence of VEGF-C in these mice can compensate for the absence of VEGF-D during development. In contrast, VEGF-D overexpression has been shown to increase tumor lymphangiogenesis and metastasis [70,71]. Recently, the overexpression of VEGF-D specifically in the kidneys has been demonstrated to augment the density of renal lymphatics [72].…”