Relationship Between VEGF-C, VEGFR-3Expression And Lymphangiogenesis, Lymph Node Metastasis In Colorectal Carcinoma

Objective: Colorectal cancer ia a common gastrointestinal malignantdisease for which lymphatic system and hematogenous system are the primarypathway of metastasis. The extent of lymph node involvement is a keyprognostic for the patient's outcome. In the past years, however, due todifficulty in studing lymphatic vessels because of a lack of lymphatic-specificmarkers, the study of lymphatic metastasis lagged behind the hematogenousstudy and the exact mechanism of lymph node metastasis is poorly understood.In recent years, with the rapid development of molecular biology especiallythe identification of lymph angiogenesis factor and lymphatic endothelialmarkers, the study of lymph angiogenesis in tumor attracted more and moreattention and has been becoming the hot spot in this filed. Vascular endothelialgrowth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3(VEGGR-3) are the two lymph angiogenesis promoting factors. The aim ofthis study was to provide the theoretical basis of lymphatic metastasis andbiotherapeutic targets for colorectal cancer by means of the expression level ofVEGF-C and VEGGR-3in colorectal cancer tissues and analysis of itsrelationship with clinicopathological features.Methods: Fifty colorectal cancer tissues and twenty colorectal adenomatissues were selected randomly, meanwhile twenty normal colorectal tissueswere selected as negative control group. Immuohistochemistry was used todetect the expression of VEGF-C and VEGFR-3in colorectal cancer,colorectal adenoma and normal mucosa tissues. Simultaneously, lymphaticvessel density (LVD) was evaluated with lymphatic endothelium-specificmarker, lymphatic vessel endothelial hyaluronan receptor-1(LYVE-1), andanalyze its relationship with clinicopathological features. In addition, Fifty colorectal cancer tissues and fifty normal mucosa surrounding tumor tissueswere selected, the expression of VEGF-C and VEGFR-3mRNA in tumorspecimens and normal mucosa surrounding tumor specimens were examinedby Real-time polymerase chain reaction (Real time RT-PCR) and analyze itsrelationship with clinicopathological features.Results: The positive rates of VEGF-C and VEGFR-3expression intumor specimens were42%and44%, respectively. However, VEGF-C andVEGFR-3expressions were not found in colorectal adenoma specimens andnormal mucosa specimens. The expression of VEGF-C and VEGFR-3intumor specimens were closely correlated with lymph node matastasis (P<0.01),but not with patient's age, gender, TNM stage, Dukes stage, tumor location,cellular differentiation, histological type and depth of invasion(P>0.05). LVDswere significantly higher in VEGF-C-positive and VEGFR-3-positive tumorscompared with VEGF-C-negative and VEGFR-3-negative tumors (P<0.001).Univariate and multivariate analysis revealed that VEGF-C(P＜0.01,P=0.016)and VEGFR-3(P＜0.01,P=0.041) were the independent factors associatedwith lymph node metastasis. In tumor specimens and normal mucosasurrounding tumor specimens, the expression of VEGF-C mRNA were-2.65±0.83and-2.45±0.72(P＞0.05), respectively; the expression ofVEGFR-3mRNA were-2.92±1.15and-2.73±1.07(P＞0.05). The expressionof VEGF-C and VEGFR-3mRNA in tumor specimens were closely correlatedwith lymph node matastasis (P=0.021) and invasion depth (P=0.014), but notwith patient's age, sex, TNM stage, Dukes stage, histological type,differentiation degree and tumor location (P＞0.05). In tumor specimens, therewas a high positive correlation between VEGF-C and VEGFR-3mRNAexpressions (r=0.51, P＜0.01).Conclusions: This study suggests that the expression of VEGF-C andVEGFR-3contributed to lymphangiogenesis and lymph nodal metastasis incolorectal cancer, although the expression of VEGF-C and VEGFR-3mRNAin tumor specimens and normal mucosa surrounding tumor specimens werenot significantly different. This inconsistency infered that lymphangiogenesis may be the result of specific gene regulation before metastasis and theformation of local tumor micrometastases is the "base camp" for colorectalcancer patients with lymph node metastasis, but lymphangiogenesis still canserve as a new target of biological therapy in colorectal cancer.