Challenges of chimeric antigen receptor-T/natural killer cell therapy in the treatment of solid tumors: focus on colorectal cancer and evaluation of combination therapies.

Colorectal cancer (CRC) is the second most common cancer globally and one of the deadliest human malignancies. Traditional therapies, such as surgery, chemotherapy, and combination therapies have been used to treat patients with CRC. However, recently immunotherapy has been considered a practical and attractive therapeutic approach in various cancers, such as CRC. Among the immunotherapy methods, chimeric antigen receptor (CAR)-T, and CAR-natural killer cells (NK) cells therapy have been significantly successful, mainly in treating hematological malignancies. However, the effectiveness of CAR-T/NK cell therapy in the treatment of solid tumors, such as CRC has been less than blood malignancies due to various challenges, such as the selection of tumor antigens, lack of proper trafficking in tumor tissue, immunosuppressive tumor microenvironment, tumor heterogeneity and, adverse effects during and after CAR-T/NK cell therapy. This review summarized the biological structure of CAR-T/NK cells and their use in various types of human malignancies, particularly CRC, as well as the challenges of this type of treatment and the outcome of related combination therapies.

DCE-MRI radiomics models predicting the expression of radioresistant-related factors of LRP-1 and survivin in locally advanced rectal cancer.

Objective: Low-density lipoprotein receptor-related protein-1 (LRP-1) and survivin are associated with radiotherapy resistance in patients with locally advanced rectal cancer (LARC). This study aimed to evaluate the value of a radiomics model based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the preoperative assessment of LRP-1 and survivin expressions in these patients. Methods: One hundred patients with pathologically confirmed LARC who underwent DCE-MRI before surgery between February 2017 and September 2021 were included in this retrospective study. DCE-MRI perfusion histogram parameters were calculated for the entire lesion using post-processing software (Omni Kinetics, G.E. Healthcare, China), with three quantitative parameter maps. LRP-1 and survivin expressions were assessed by immunohistochemical methods and patients were classified into low- and high-expression groups. Results: Four radiomics features were selected to construct the LRP-1 discrimination model. The LRP-1 predictive model achieved excellent diagnostic performance, with areas under the receiver operating curve (AUCs) of 0.853 and 0.747 in the training and validation cohorts, respectively. The other four radiomics characteristics were screened to construct the survivin predictive model, with AUCs of 0.780 and 0.800 in the training and validation cohorts, respectively. Decision curve analysis confirmed the clinical usefulness of the radiomics models. Conclusion: DCE-MRI radiomics models are particularly useful for evaluating LRP-1 and survivin expressions in patients with LARC. Our model has significant potential for the preoperative identification of patients with radiotherapy resistance and can serve as an essential reference for treatment planning.

Towards exertion of immunotherapeutics in the treatment of colorectal cancer; adverse sides, challenges, and future directions.

Immunotherapy has growingly been prosperous as a promising therapeutic option for several kinds of solid tumors, such as colorectal cancer (CRC), subsequent to initial successful outcomes in the treatment of melanoma. The use of immunotherapy, like nivolumab and pembrolizumab (which are monoclonal antibodies against programmed cell death 1) has shown prosperous outcomes in a group of CRC patients who represent mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H). However, a successful outcome of treatment by immune checkpoint inhibitors (ICIs) has not been observed in all of the metastatic CRC patients with dMMR-MSI-H tumors. ICIs are able to block the co-inhibitory signaling transduced in T cells, resulting in increased cytotoxic activity of T cells and efficient killing of tumor cells. In spite of availability of diverse immunotherapeutics in treatment of advanced CRC, a poor survival rate of such approaches has been reported along with challenges in the clinical practice. It is necessary to identify novel biomarkers and molecular signatures to approximate the outcome of ICI therapy in the metastatic CRC patients with dMMR-MSI-H tumors. Here we tried to clarify the current line of evidence regarding immunotherapeutics in the treatment of CRC, and discuss the challenges and hurdles in the management of these patients.

IGF1/IGF1R and microRNA let-7e down-regulate each other and modulate proliferation and migration of colorectal cancer cells.

MicroRNA let-7 has been reported to be down-regulated in several human cancers and is now characterized as a tumor suppressor. IGF1R is over-expressed in many cancers and IGF1/IGF1R pathway is attractive target for anticancer therapy. However, the crosstalk between let-7 and IGF1/IGF1R are largely unknown. The present study showed IGF1R were significantly over-expressed in colorectal cancer tissues compared with adjacent normal tissues through immunohistochemical analysis. qRT-PCR results showed that let-7a, let-7b and let-7e were down-regulated in colorectal cancer tissues. Bioinformatics analysis revealed that both IGF1 and IGF1R mRNA are potential targets for let-7 miRNA family. Ectopic transfection of let-7e led to a significant reduction in IGF1R at protein level and their downstream Akt inhibition, as well as a reduction in cell proliferation, migration and invasion in colorectal cancer cells, while inhibition of let-7e enhanced the expression of IGF1R. On the other hand, IGF1 stimulation can significantly down-regulate the expression of let-7e in colorectal cancer cells. Taken together, our findings identify a negative feedback regulation between let-7e and IGF1/IGF1R, and suggest that let-7e could be used in IGF1R-targeted therapeutics in anticancer therapy. ABBREVIATIONS: IGF1: insulin-like growth factor 1; IGF1R: IGF1 receptor; miRNA: microRNA; CRC: colorectal cancer; EGFR: epidermal growth factor receptor; HRP: horseradish peroxidase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; p-Akt: phospho-Akt; PI3K: phosphoinositide 3-kinase; qRT-PCR: quantitative reverse transcription-PCR; IHC: immunohistochemical; siRNA: small interfering RNA; 3'-UTR: 3'-untranslated region.

MicroRNA-194 inhibits the epithelial-mesenchymal transition in gastric cancer cells by targeting FoxM1.

AIM: We hypothesized that miR-194 may control Forkhead box protein M1 (FoxM1) expression in gastric cancer cells and therefore may have therapeutic potential in gastric cancer. METHODS: The expression level of miR-194 was examined using real-time PCR in human gastric cancer and noncancerous gastric tissues, gastric cancer cell and normal gastric mucosal epithelial cell. We examined whether the miR-194 regulates cell migration and invasion, and the epithelial-mesenchymal transition Phenotype by inhibiting FoxM1 in gastric cancer cells. RESULTS: The expression of miR-194 was significantly lower in gastric cancer compared with non-cancerous gastric tissues and cells. Exogenous expression of miR-194 inhibited cell migration, invasion, and the epithelial-mesenchymal transition phenotype in gastric cancer cells. Moreover, we discovered a novel post-transcriptional regulatory mechanism of FoxM1 expression that is mediated by miR-194. CONCLUSION: Our study clearly demonstrates that miR-194 inhibits the acquisition of the EMT phenotype in gastric cancer cells by downregulating FoxM1, thereby inhibiting cell migration and invasion during cancer progression.

The association between RAD23B Ala249Val polymorphism and cancer susceptibility: evidence from a meta-analysis.

BACKGROUND: A number of studies have investigated associations of genetic variation in RAD23B Ala249Val (rs1805329 C>T) with cancer susceptibility; however, the findings are inconsistent. We performed a meta-analysis to acquire a more precise estimation of the relationship. METHOD: We searched literatures from PubMed, Embase and Web of Science. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association between Ala249Val polymorphism and cancer risk. RESULTS: A total of 23 studies consisting of 10837 cases and 13971 controls were included in this meta-analysis. Overall, no significant associations were found between RAD23B Ala249Val polymorphism and cancer risk (Val/Val vs. Ala/Ala: OR = 0.97, 95% CI = 0.75-1.25; Ala/Val vs. Ala/Ala: OR = 1.08, 95% CI = 0.96-1.22; recessive model: OR = 0.93, 95% CI = 0.76-1.14 and dominant model: OR = 1.07, 95% CI = 0.94-1.20). We did not find any significant associations in the further stratification analyses by cancer type, ethnicity and source of control. CONCLUSIONS: Despite some limitations, this meta-analysis indicates that it is unlikely that the RAD23B 249Val/Val polymorphism may contribute to the individual susceptibility to cancer risk. However, further advanced designed studies with larger sample size and different ethnicities should be conducted to confirm our results.

Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population.

OBJECTIVE: To investigate the association between a single nucleotide polymorphism rs2274223 (adenine [A] to guanine [G]) in the phospholipase C epsilon 1 (PLCE1) gene and susceptibility to colorectal cancer (CRC). METHODS: The PLCE1 rs2274223 polymorphism was genotyped in patients with CRC and age- and sex-matched cancer-free control subjects from a Chinese population in a case-control study. PLCE1 mRNA levels in pair-matched tumour and adjacent noncancerous tissue were evaluated by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: A total of 417 patients with CRC and 416 control subjects were enrolled in the study. The AG and GG genotypes of PLCE1 rs2274223 were associated with a significantly increased risk of CRC (for AG + GG versus AA: adjusted odds ratio 1.52, 95% confidence interval 1.15, 2.00). PLCE1 mRNA levels were significantly lower in tumours than in adjacent noncancerous tissue. Lower levels of PLCE1 mRNA were observed in both AG and GG genotype carriers compared with the AA genotype carriers. CONCLUSIONS: These results indicate that the PLCE1 rs2274223 A > G change might reduce gene expression and that the variant G genotype might contribute to the increased risk of CRC.

Total mesorectal excision for rectal cancer: laparoscopic versus open approach.

AIMS AND BACKGROUND: To evaluate the oncologic safety of laparoscopic total mesorectal excision for rectal cancer. Methods and study design. Patients who underwent laparoscopic (n = 256) or open (n = 173) total mesorectal excision for rectal cancer between June 2005 and June 2011 were included. Long-term survival operative data and postoperative recovery were retrospectively reviewed from a prospectively collected database. RESULTS: No significant difference was found between the two groups in terms of age, sex, tumor stage and preoperative comorbidities. Twelve patients were converted to open procedures. Differences were found in blood loss (55 ± 14.1 vs 152 ± 29.2 ml P <0.05), infection of incision (3.1% vs 12.7%, P <0.05) and postoperative stay (8.1 ± 3.0 vs 12.4 ± 6.3 days, P <0.05). Both groups were comparable regarding lymph node clearance specimen length and distal margin. There was no significant difference in overall survival between the two groups by the life-table method. However, operative time in the laparoscopic group was longer than in the open group (168 ± 27.6 vs 141 ± 21.9 min, P <0.05). CONCLUSIONS: Laparoscopic total mesorectal excision for rectal cancer offers oncologic results similar to those obtained with the open procedure with a favorable short-term outcome. Continued use of the procedure in these patients is supported.

Heterogeneity-related anticancer therapy response differences in metastatic colon carcinoma: new hints to tumor-site-based personalized cancer therapy.

BACKGROUND/AIMS: Heterogeneity in primary tumor and related metastases may result in different response to anticancer therapy. Previous work revealed that there were heterogeneity in primary colon carcinoma and matched lymphatic and hepatic metastases. Whether such heterogeneity in primary colon carcinoma and corresponding lymphatic and hepatic metastases would result in different response to anticancer therapy is unknown. METHODOLOGY: To investigate whether the heterogeneity in primary colon carcinoma and matched lymphatic and hepatic metastases would result in different response to anticancer therapy, patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases were used to evaluate the response to VEGF-targeted therapy (bevacizumab) in combination with chemotherapy (capecitabine). RESULTS: All xenografts of primary colon carcinoma and corresponding lymphatic and hepatic metastases in nude mice responded to VEGF-targeted therapy in combination with chemotherapy. However, chemotherapy alone resulted in significantly higher tumor growth inhibition rate in xenogfafts of primary colon carcinoma than that of corresponding lymphatic and hepatic metastasis (p < 0.01). VEGF-targeted therapy in combination with chemotherapy resulted in significantly higher tumor growth inhibition rate in xenogfafts of colon carcinoma lymphatic metastasis than that of corresponding primary colon carcinoma and hepatic metastasis (p < 0.001). CONCLUSIONS: Our results demonstrate that primary colon carcinoma and its corresponding lymphatic and hepatic metastases have different response rate to chemotherapy and to VEGF-targeted therapy in combination with chemotherapy. This study provides us new hints to tumor-site-based personalized cancer therapy in metastatic colon carcinoma.