CRABP1 (cellular retinoic acid binding protein 1) belongs to the family of fatty acid binding proteins. Retinoic acid binding is the only known functional activity of this protein. The role of CRABP1 in human carcinogenesis remains poorly understood. Here, for the first time we demonstrated pro-metastatic and pro-tumorigenic activity of CRABP1 in mesenchymal tumors. Further functional analysis revealed that the pro-tumorigenic effect of CRABP1 does not depend on retinoic acid binding activity. These results suggest that CRABP1 could have an alternative intracellular functional activity that contributes to the high malignancy of transformed mesenchymal cells. Microarray analysis detected CRABP1-mediated alterations in the expression of about 100 genes, including those encoding key regulatory proteins. CRABP1 is ubiquitously expressed in monophasic synovial sarcomas, while in biphasic synovial sarcomas it is expressed uniquely by the spindle cells of the aggressive mesenchymal component. High level of CRABP1 expression is associated with lymph node metastasis and poor differentiation/high grade of pancreatic neuroendocrine tumors (pNETs). Presented data suggest CRABP1 as a promising biomarker of pNETs' clinical behavior. Our results give the first evidence of pro-tumorigenic and pro-metastatic activity of CRABP1 in mesenchymal and neuroendocrine tumors.

Serum levels of insulin-like growth factors (IGF-1 and IGF-2), IGF-binding proteins (IGFBP-1, IGFBP-2, and IGFBP-3) and vascular endothelial growth factor (VEGF) were measured by standard ELISA technique in 95 primary colorectal cancer patients and 48 healthy individuals. Significant increase in serum levels of IGF-1, IGFBP-2, and VEGF and decrease in IGFBP-3 level were demonstrated in patients in comparison with the control group; in male patients, serum level of IGF-2 was also increased. Sensitivity of IGF-1 as the prospective diagnostic marker of colorectal cancer was 80% and specificity was 75% at the threshold level of 140 ng/ml. Serum levels of IGF-1 significantly decreased with age in both patients and healthy donors, but in patients, this correlation was much weaker. These parameters did not correlate with the main clinical and morphological indices, such as dissemination, localization, and histological structure of colorectal cancer.

Immunohistochemical analysis of the expression of E-cadherin, beta-catenin, and CD-44v6 proteins was carried out for evaluating the metastatic potential of colorectal cancer cells. Specific features of expression, distribution, and interactions of adhesive molecules in primary tumors of the large intestine and their metastases in the liver and lymph nodes were studied. Reduction and complete absence of E-cadherin expression were much more often observed in patients with colorectal cancer with metastases in the liver than in patients without metastases. Cytoplasmic immunoreactivity and nuclear translocation of beta-catenin were increased in more than 80% cases with colorectal adenocarcinoma with metastases. These changes in the expression of E-cadherin and beta-catenin in tumor cells can be regarded as factors of unfavorable prognosis of colorectal cancer. No significant relationship between expression of CD-44v6 protein and metastatic potential of cancer cells was detected.

We performed a parallel evaluation of the status of epidermal growth factor receptors EGFR and HER-2 in tumor samples from 31 patients with squamous cell carcinoma of the esophagus. Hyperexpression of proteins was detected by immunohistochemical methods and gene amplification and other chromosome abnormalities were studied using FISH reaction. Evaluation of EGFR status showed that amplification of EGFR gene was present in 25% cases and chromosome 7 polysomy was detected in 29.2% cases positive by protein expression (2+/3+). Immunohistochemically positive EGFR status was confirmed by the results of FISH reaction for gene amplification and chromosome 7 polysomy in 54.2% cases (p=0.002). During evaluation of HER-2 status in the tumor, hyperexpression of the protein detected histochemically was not confirmed by FISH reaction for detection of amplification of the corresponding gene in 16.1% cases. In 22.6% patients, chromosome 7 polysomy was detected; it was not accompanied by amplification of HER-2 gene, but was related to immunohistochemically positive status of the tumor. Hyperexpression of EGFR protein significantly correlated with the presence of intravascular invasion (p=0.006) and increased depth of invasion (p=0.044), while amplification of EGFR gene (≥2.2) correlated with low differentiation degree of the tumor (p=0.006). The outcome of the disease was not associated with EGFR status at the gene and protein levels, whereas clinical course of the disease in patients with immunohistochemically negative expression of HER-2 protein was more favorable than in patients with positive expression (p=0.004). The results of this study suggest that hyperexpression/amplification of EGFR and hyperexpression of HER-2 are important clinical markers for evaluation of disease prognosis and development of new regimens of targeted therapy for patients with squamous cells carcinoma of the esophagus.