The Clinical Significance of Serum no and TGF-β1 in patients with Colon Polyps and Colorectal Cancer

Colorectal polyps are quite common in western countries and have been found in more than 30% of autopsied people over 60 years of age^12,13. The most important factor determining the prevalence of colon adenomas is age and the incidence of adenomas increases over the age of 50. The prevalence is higher in the male population (M/F= 1.4/1) than in females (14). In our study, the mean age of 30 patients with colorectal polyps was 55.5 ± 11 years (39-84). Nineteen (63.4%) of the patients were male and 11 (36.6%) were female (M/F=1.7/1).

Similar to colon polyps, the frequency of colorectal cancers increases in direct proportion to age. Colorectal cancers are more common in men and mostly over 50 years of age. The peak incidence is in the 6^th and 7^th decades. Hereditary colon cancers such as familial adenomatous polyposis (FAP) can also be seen at earlier ages¹⁴. In our study, the mean age

of 28 patients with colorectal cancer was 58.9 ± 11.8 years (42-83). Fourteen (50%) of the patients were male and 14 (50%) were female (M/F- 1/1). Although colorectal cancers are more

common in males in previous studies, we found the rates of males and females to be equal in our study. Since colorectal cancers can be observed below the age of 50 years, screening tests

should be performed at an earlier age in the presence of predisposing factors such as family history of colon cancer, inflammatory bowel disease or FAP¹⁴.

In our study, 8 (28.57%) of the patients with colorectal cancer were under the age of 50 years and 5 (62.5%) of them were female patients. However, none of the patients with colorectal cancer under the age of 50 years in our study had a family history or genetic predisposition such as FAP. The fact that colon cancers can be seen in sporadic cases under the age of 50 years suggests that screening tests should be performed more commonly and at earlier ages.

Carcinogens activated by cooking methods of foods, increased mutagenic activity in feces, excessive alcohol consumption and heavy smoking are risk factors that increase the development of colon polyps and cancer¹⁵. In our study, 6 (21.4%) of patients with colorectal cancer and 6 (20%) of patients with colon polyps were smokers.

Of neoplastic polyps, 80-86% are tubular, 8-16% tubulovillous, and 3-16% villous adenomas¹⁶. In our study, 17 (56.6%) of the polyps were tubular, 7 (23.3%) were tubulovillous and 6 (20%) were villous. Tubular adenomas were less and villous adenomas were more in our study group compared to the literature.

Simple small (<1 cm) tubular adenomas are quite common and have a low risk of malignancy. In our study, 13 of 30 cases (43.3%) with polyps were smaller than 1 cm. Advanced adenomas are polyps >1 cm and contain a high rate of villous tissue or high grade dysplasia¹⁵. In our study, 17 (56.6%) of 30 patients with polyps were larger than 1 cm.

Adenomas are mostly localized distally. This region is also the region where colorectal cancer is localized most frequently. Especially in individuals aged 60 years and older, adenoma localization shifts proximally¹⁷. In our study, 17 (56.6%) of the polyps were localized in the

rectum, 5 (16.7%) in the sigmoid colon, 5 (16.7%) in the ascending colon and 3 (10%) in the transverse colon. In cancerous cases, 21 (75%) were localized in the rectum, 3 (10.7%) in the

sigmoid colon, 2 (7.1%) in the transverse colon, 1 (3.57%) in the ascending colon and 1 (3.57%) in the cecum. In accordance with previous studies, we observed a parallelism in the localization of cancers and polyps.

CEA and CA 19-9 are the most commonly used tumor markers in the diagnosis and follow-up of colorectal cancers. In general, CEA is used in the evaluation of response to treatment and in the detection of postoperative recurrences and metastases in colorectal cancers¹.

In our study, when colon cancer, colon polyps and control group were compared in terms of CEA levels, serum CEA levels were found to be significantly higher in patients with colorectal cancer compared to polyps and healthy control group (p<0.05). Although CEA levels were higher in patients with colon polyps compared to the control group, group, it was not statistically significant.

CA 19-9 is a high molecular weight antigen detected by monoclonal antibodies that plays a role in cancer invasion and metastasis. It is most frequently elevated in pancreatic and biliary tumors, as well as in patients with colorectal cancer. On the other hand, high serum CA 19-9 levels can also be observed in many nonneoplastic benign diseases¹⁸.

When colorectal cancer, colon polyp and control groups were compared in terms of CA 19-9 levels, the elevated CA 19-9 levels in the colon cancer group were found to be statistically significant compared to the colon polyp and control groups. There was no statistically significant difference between the colon polyp group and the control group in terms of CA 19- 9 levels. Since CA 19-9 is an antigen that plays a role in invasion and metastasis, its sensitivity is low in early stage colorectal cancers and adenomas. In our study, we found elevated serum CA 19-9 levels in colorectal cancer patients in accordance with the literature. However, we found no significant difference between patients with colorectal polyps and normal healthy group.

Nitric oxide (NO) is a mediator involved in many biological events such as vasodilation neurotransmission, angiogenesis, apoptosis and tumor progression. Recent studies have investigated NO expression and activity in human cancers¹⁹. However, NO expression in colorectal cancers is still controversial. In many studies, NO expression and activity were found to be increased in tumor tissue compared with normal mucosa, while some studies have reported the opposite results. While low levels of NO concentration accelerate tumor growth and angiogenesis, high concentrations of NO have been found to show antitumor activity by inducing cytotoxicity and apoptosis²⁰.

Many in vitro and in vivo studies have shown that NO accelerates tumor angiogenesis. NO has been shown to induce endothelial cell growth and regulate tumor blood flow. Ziche et al. have shown that NO controls angiogenesis by modulating some angiogenic factors such as vascular endothelial growth factor released from tumor cells ²¹. In another study, when NO expression or NO enzyme activity was examined in tissue samples, NO expression was found at very low levels in normal colonic epithelium, while NO expression was found at high levels in 60% of adenomas and 20-25% of cancers. While NO activity was found at very low levels in normal tissue adjacent to neoplastic lesions, the highest levels were found in adenomas²².

Lagares et al. showed that tumor metastasis was higher and long-term survival was significantly lower in the group with higher NO activity in colon cancers ²³.

In our study, although serum NO levels were found to be lower in patients with colorectal cancer compared to patients with polyps and control group, no statistically significant difference was found between the three groups in terms of serum NO levels. This finding suggests that low NO expression may be a negative prognostic factor in tumor progression.

In our study, although not statistically significant, NO levels in the control group and patients with colon polyps were higher than in patients with colorectal cancer. Further studies are needed to clarify the controversial results regarding NO expression in colorectal tumors and to determine the relationship between NO levels in adenomas and tumor progression.

TGF-β is a family of growth factors with many functions. TGF- β1 is released by platelets and synthesized by a variety of normal cells including activated lymphocytes, macrophages and neutrophils, as well as many transformed cells. TGF- β is thought to be involved in epithelial carcinogenesis. Many tumor cells including colorectal cancer express TGF-β and have been reported to play a role in tumor progression and metastasis development²⁴.

It was found that TGF- βl expression was closely related to disease progression and survival in colorectal cancer patients, the 3-year survival rate was 80% in TGF- β negative tumors and 40% in TGF- β positive tumors, and it was reported that serum TGF- β1 levels were <5ng/ml in normal healthy individuals, <7.5 ng/ml in benign colonic lesions and >7.5 ng/ml in colorectal cancers. They also showed that high preoperative TGF- β1 levels may be a determining factor for liver metastasis after curative resection^24,25.

Narai et al. found that plasma TGF- β1 concentrations were significantly higher in patients with colorectal cancer compared to healthy volunteers. It was also reported that serum TGF- β1 levels were closely related with the depth of tumor invasion, lymph node metastasis distant metastasis and serum CEA levels and decreased significantly after surgical resection of the tumor²⁶.

In our study study, the difference in serum TGF- β1 levels between colorectal cancer patients and healthy control group was statistically significant (p-<0.05). However, no statistically significant difference was found between colorectal cancer and colon polyps. In addition, although serum TGF- β levels were lower in tubular adenomas, no statistically significant difference was found between villous, tubulovillous and tubular adenomas (p>0.05).

The finding that serum TGF- β1 levels are higher in patients with colon cancer compared to normal healthy group suggests that TGF- β may play a role in colorectal carcinogenesis. In screening of patients with colorectal cancer, serum CEA levels can be found normal in approximately 30% of patients. Therefore, the use of TGF- β1 as a tumor marker in the follow-up of colorectal cancer patients with normal serum CEA levels may be clinically useful.

CEA, CA 19-9 and TGF-β1 levels were found to be significantly higher in colorectal cancer compared to colon polyp and control groups. There was no significant difference between the three groups in terms of NO levels. Again, CEA, CA 19-9, NO and TGF-β1 levels were not significantly higher in colon polyps.

In conclusion, all these data suggest that NO and TGF- β1 are effective in the development of colorectal cancer and that the use of TGF- β1 as a tumor marker in the follow- up of colorectal cancer patients with normal CEA and CA 19-9 levels may be clinically useful. It suggests that NO may play a critical role in molecular pathways in the progression of colon

adenoma to colon cancer and that the use of CEA, CA 19-9, NO and TGF-β1 in the monitoring of adenomatous polyps, a risk factor for colorectal cancer development, may not be appropriate.