VEGF-A, VEGF-C, and VEGF-D in Colorectal Cancer Progression

Abstract

We aimed to assess the relationship of the angiogenic cytokines VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFR-2 and VEGFR-3 in the adenoma-carcinoma sequence and in metastatic spread of colorectal cancer (CRC). mRNA expression levels were measured using semi-quantitative reverse transcription polymerase chain reaction in 70 CRC (35 with paired mucosae) and 20 adenomatous polyps. Immunohistochemistry and ELISA assessed protein expression. VEGF-D mRNA expression was significantly lower in both polyps and CRCs compared with normal mucosa (P=.0002 and.002, respectively), whereas VEGF-A and VEGF-C were significantly raised in CRCs (P=.006 and.004, respectively), but not polyps (P=.22 and P=.5, respectively). Receptor expression was similar in tumor tissue and normal mucosae. Tumors with lymph node metastases had significantly higher levels of VEGF-A compared with non-metastatic tumors (P=.043). There was no association between VEGF-C or VEGF-D and lymphatic spread. The decrease in VEGF-D occurring in polyps and carcinomas may allow the higher levels of VEGF-A and VEGF-C to bind more readily to the VEGF receptors, and produce the angiogenic switch required for tumor growth. Increased expression of VEGF-A within CRCs was associated with lymphatic metastases, and therefore, this member of the VEGF family may be the most important in determining metastatic spread.

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

“…Patterns of VEGF-C mRNA expression were similar in the primary tumour and lymphatic metastases. The mRNA findings of the study were confirmed by immunohistochemistry, which showed no correlation between positive staining for VEGF-A, VEGF-C or VEGF-D and lymphatic spread (George et al, 2001). Further analyses of VEGF family mRNA levels in the adenoma -carcinoma sequence showed that of VEGF-A, VEGF-B and VEGF-C, only VEGF-A mRNA levels were consistently raised in invasive malignancy and this became apparent early on in disease progression, as levels were elevated to a similar extent in tumours with and without lymph node metastases or distant spread (Andre et al, 2000).…”

“…Tumour expression, assessed by RT-PCR, of VEGF-D mRNA was less than in normal tissue (George et al, 2001), while White et al (2002) found higher levels of VEGF-D protein expression in cancers detected by immunohistochemistry. The increased VEGF-D protein levels detected were associated with lymph node involvement and reduced overall and disease-free survival (White et al, 2002).…”

“…Studies examining mRNA levels of various VEGF family members tend to show a lack of association with clinicopathological factors. George et al (2001) showed an increase in VEGF-A and VEGF-C mRNA in carcinomas (P ¼ 0.006 and P ¼ 0.004, respectively) but not in colonic polyps (P ¼ 0.22 and 0.5, respectively). No association was found between the increased level of VEGF-C mRNA and lymph node status, although a positive relationship existed between positive lymph nodes and VEGF-A mRNA expression.…”

CD147 regulates vascular endothelial growth factor—A expression, tumorigenicity, and chemosensitivity to curcumin in hepatocellular carcinoma

“…VEGF-A is previously known to act as a specific blood angiogenic factor. However, recent studies have shown that VEGF-A plays a principle role in tumor progression and lymphatic metastasis (19,20). Here, we used RNAi to downregulate directly the expression of CD147 in Hepa1-6 cells.…”

Lymphangiogenesis in colorectal cancer—Prognostic and therapeutic aspects

“…93,94 Although a number of reports show a positive correlation between VEGF-C and VEGF-D over expression and lymph node metastases in CRCs, [61][62][63][64][65][66]70,71 other studies do not show such relationships. [95][96][97] However, based on strong experimental studies showing a positive correlation between VEGF-C or VEGF-D expression with lymph node metastases (see Table I), it seems clear that both VEGF-C and VEGF-D may contribute to the disease course in CRC.…”