Cancer Research and Treatment

Original Articles

Participation of CCL1 in Snail-Positive Fibroblasts in Colorectal Cancer Contribute to 5-Fluorouracil/Paclitaxel Chemoresistance: Ziqian Li, Kaying Chan, Yifei Qi, Linlin Lu, Fen Ning, Mengling Wu, Haifang Wang, Yuan Wang, Shaohui Cai, Jun Du; Cancer Res Treat. 2018;50(3):894-907. Published online September 18, 2017; DOI: https://doi.org/10.4143/crt.2017.356

Abstract PDF Supplementary Material PubReader ePub

Purpose
Cancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized.
Materials and Methods
Snail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap.
Results
Snail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor β/nuclear factor-κB signaling pathways.
Conclusion
Taken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.

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Expressions of Multidrug Resistance-Related Genes in Gastric Cancer Tissue and Normal Gastric Mucosal Tissue: Seok Hun Song, Sang Woon Kim, Sun Kyo Song, Joon Hyuk Choi, Jeoung Hee Ha, Kyung Hee Lee; Cancer Res Treat. 2001;33(4):302-308. Published online August 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.4.302

Abstract PDF: PURPOSE
This study was conducted to evaluate the expressions of the mdr1 gene and the MRP gene in tumor and adjacent normal gastric tissues.
MATERIALS AND METHODS
The specimens were obtained from 53 patients who had gastric cancer. None of these patients had received any kind of preoperative chemotherapy. The reverse transcription polymerase chain reaction and immunohistochemical stain were used to check the level of expressions of mRNAs and their associated proteins.
RESULTS
Highly positive expressions of mdr1 mRNA, MRP mRNA, p-glycoprotein, and MRP (multidrug resistance associated protein) were observed in the tumor and the adjacent normal tissues. Most tumor tissues coexpressed mdr1 mRNA and MRP mRNA significantly (p<0.001). The expression of these genes in the tumor was much stronger than in the normal counterpart tissues. The expression of the p-glycoprotein was correlated only with the pathological stage (p<0.05). MRP expression was correlated with lymph node metastasis (p<0.05).
CONCLUSION
Normal gastric tissue showed strong physiologic expressions of the mdr1 and MRP genes. Overexpressions of these genes were observed in gastric cancer tissue. The presence of multidrug resistance should be considered when planning anticancer chemotherapy for treating gastric cancer.

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Clinicopathologic Significance of Multidrug Resistance Protein Expression in Patients with Stage III Gastric Adendegrees Carcinoma: Sae Hyun Kim, Wan Ku Lee, Hyun Kim, Young Nam Kim, Seung Min Park, Su Jin Choi, Hyo Suk Park, Myung Jin Joo, Kwang Min Lee, Jong Myung Lee, Sung Hye Shin, Min Chul Kim; J Korean Cancer Assoc. 2000;32(3):487-496.

Abstract PDF: PURPOSE
We wanted to determine the prognostic significance of P-glycoprotein (Pgp) and multi drug resistance-assdegrees Ciated protein (MRP) in stage III gastric adendegrees Carcinoma by evaluating whe ther the Pgp and/or MRP expression correlate with various clinicopathological parameters and survival rates. MATERIAL AND METHODS: The expression of Pgp and/or MRP were studied immunohistdegrees Chemi cally by ABC method with paraffin-embedded tissue specimens which were surgically obtained from 64 cases of stage III gastric adendegrees Carcinomas at the Department of Surgery, Presbyterian Medical Center from 1991 to 1992. Statistical differences of both expression in various factors including survival rates and clinicopatholgical parameters were sought.
RESULTS
Expression rates of Pgp and MRP group were 50.0% and 43.7% respectively. There was no significant correlation between expression of two proteins and various clinicopathological variables such as age, sex, stage, tumor depth, number of metastatic node, tumor size, site and method of operation. However, in case of the degree of differenciation, the expression of Pgp and/or MRP was significantly greater in well differenciated adendegrees Carcinoma than in poorly dif ferenciated adendegrees Carcinoma (p=0.001, p=0.012). Statistically, no significant correlations between the expression of Pgp and/or MRP and overall survival rates were found.
CONCLUSION
These results suggest that the Pgp and/or MRP expression in patients with stage III gastric adendegrees Carcinomas are not useful in determining postoperative chemotherapy and as an independent predictor of survival.

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Reversal of ( MDR ) Multidrug resistance ) in Adiamycin - Resistant MCF - 7 Cells by Tamoxifen : Possible Role of Protedin Kinase ( PCK ): Han Lim Moon, Hoon Kyo Kim, Kyung Shik Lee; J Korean Cancer Assoc. 1994;26(2):242-249.

Abstract PDF: Introduction: MDR(multidrug resistance), which is caused by mdr gene and its product, p-gly- coprotein, is one of the most important obstacles during cancer chemtherapy. Recently, many efforts to reverse MDR have been done and partly applied in clinic. Verapamil, quinidine, dipyridamole and cyclosporine were the representative ones and tamoxifen and toremifene have been known as those kinds. On the other hand, protein kinase c(PKC) has a critical role in cell proliferation and differentiation and also associated with MDR. Using wild type and adriamycin-resistant type of MCF-7(MCF-7/WT and MCF-7/ADM), we found antiestrogen, tamoxifen, had a synergistic cytotoxic effect with adriamycin on MCF-7/ADM, not on MCF-1/ WT. We also tried to clarify the mechanisms of synergism of tamoxifen with adriamycin, espe- cially in the viewpoint of drug uptake and PKC activity. Results: IC of adriamycin-cytotoxicity on MCF-7/WT and MCF-7/ADM was 0.2 ug/ml and 2 ug/ml, respectively. Tamoxifen moved IC of adriamycin-cytotoxicity of left in a dose-dependent manner in MCF-7/ADM, and 10 pM concentration of tamoxifen made IC 0.2 pg/ml in that cell line, which was very similar to IC in MCF-7/WT. But tamoxifen did not have synergistic cytotoxicity with adriamycin on MCF-7/WT. In drug efflux study with C14-adriamycin, tamoxifen enhanced drug uptake more than 200% in MCF-7/ADM although it markedly decreased when tamoxifen was added. There was no difference in baseline PKC activity and degree of dose-dependent inhibition on PKC activity by adriamycin in those two cell lines. Canclusion; Tamoxifen is thought to be as one of the plausible agents to reverse MDR in breast cancer. The possible mechanisms are to increase cellular uptake of adriamycin and to inhibit PKC activity.

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Reversal Effect of Antihistamines on Multidrug Resistance in Adriamycin - and Vincristine - resistant L1210 Variants: Jae Ryong Kim, Sung Yong Kim, Jeong Hee Kim; J Korean Cancer Assoc. 1995;27(1):130-138.

Abstract PDF: Intrinsic or acquired antitumordrug resistance in cancer cells is one of the major obstacles in cancer chemotherapy. Especially multidrug resistance(MDR) refers to the phenomenon where-by cells previously exposed to a single drug become resistant, simultaneously, to a range of structually and functionally unrelated agents. It is very important to overcome the drug- resistance in cancer cells for the success of chemotherapy. In order to isolate an effective chemasensitizer to overcome the drug resistance, we exam- ined the reversal effects of nine antihistamines on multidrug resistance in an adriamycin or a vincristine-resistant L1210(L1210AdR or L1210VcR) sublines, which show typical multidrug resistant phenotypes. The in vitro partial restoration of adriamycin sensitivity in L1210AdR by treatment of nontoxic doses of antihistamines was observed in astemizole, buclizine, megitazine, cetirizine, and terfenadine, in the order of their effectiveness(high to low). The sensitivity of L1210AdR to adriamycin was enhanced 13 fold when 1 uM of astemizole was present, and 8 fold in the presence of 30 uM buclizine. Astemizole and buclizine enhanced also the sensitivity to vinblastine(1160 fold and 933 fold), dactinomycin(complete reversal and 9 fold), or vinblastine (30 fold and 5 fold) in L1210AdR. However, the sensitivity to the same drugs in Ll210VcR was slightly increased in the presence af 1 uM astemizole or 30 uM buclizine. From these results, astemizole or buclizine may be used as a chemosensitizer during cancer chemotherapy. The mechanism by which astemizole or buclizine can reverse the drug resistance in L1210AdR or L1210VcR will be studied.

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