Neoadjuvant chemotherapy is linked to an amended anti-tumorigenic microenvironment in gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a frequently intervention for patients with locally advanced gastric cancer (GC). Nevertheless, its impact on the tumor immune microenvironment remains unclear. METHODS: We used immunohistochemistry to identify T-cell subpopulations, tumor-associated neutrophils (TANs), and tumor-associated macrophages (TAMs) in the GC microenvironment (GCME) among paired samples (pre-chemotherapy and post-chemotherapy) from 48 NAC-treated patients. Multiplex immunofluorescence (mIF) was performed to assess immune biomarkers, including CK, CD4, CD8, FOXP3, PD1, PD-L1, CD163, CD86, myeloperoxidase and Arginase-1 in paired samples from 6 GC patients whose response to NAC were rigorously defined. RESULTS: NAC was intricately linked to enhanced CD8+:CD4+ ratio, reduced CD163+ M2-like macrophages, augmented CD86+ M1: CD163+ M2-like macrophage ratio, and diminished FOXP3+ regulatory T cells (T-regs) and TANs density. Based on mIF, PD1+CD8+T-cells, FOXP3+T-regs, PD-L1+ TANs, and CD163+ M2-like macrophages exhibited marked reduction and greater co-localization with tumor cells following NAC. The pre-NAC FOXP3+ T-regs and CD163+ M2-like macrophages content was substantially elevated in the response cohort, whereas, the post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were intricately linked to the tumor pathologic response. We observed greater CD163+ M2-like macrophages and tumor cells co-localization following NAC, which was correlated with tumor pathologic response. Lastly, multivariate analysis revealed that post-NAC CD8+:CD4+ and CD86+ M1: CD163+ M2-like macrophage ratios were stand-alone indicators of positive patient prognosis. CONCLUSIONS: NAC converts the GCME to an anti-tumorigenic state that is conducive to enhanced patient outcome. These finding can significantly benefit the future planning of highly efficacious and personalized GC immunotherapy.

Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

A Systematic Review of the Therapeutic Potential of Resveratrol During Colorectal Cancer Chemotherapy.

BACKGROUND: The chemotherapy modality is generally used for treating colorectal cancer. However, the clinical application of chemotherapeutic drugs may be limited due to their adverse effects on normal cells/tissues and the development of cancer resistance. Using the combined treatment of chemotherapy drugs and natural bioactive compounds (such as resveratrol) can alleviate adverse drug reactions and induce synergies between the drugs. OBJECTIVE: In the current review, the potential therapeutic impacts of resveratrol during colorectal cancer chemotherapy were studied. METHODS: Based on the PRISMA guideline, we performed a systematic search in different electronic databases up to May, 2021. Following the search, 321 papers were found and then screened for eligibility. Twenty-seven papers were finally included in the present study Results: Compared to the control group, the growth inhibition of cancerous cells treated with chemotherapeutic drugs was considerably higher, and resveratrol co-administration synergistically increased chemotherapy-induced cytotoxicity. Moreover, a reduction in the tumor weight, volume and growth of mice was observed following chemotherapy administration compared to the untreated groups, and these reductions were predominant in animals treated with resveratrol plus chemotherapy. Other findings showed that chemotherapy alone and in combination with resveratrol modulated the cell cycle profile of cancerous cells. Furthermore, chemotherapy treatment induced a set of biochemical and histopathological alterations in cancer cells/tissues, and these changes were synergized following resveratrol co-treatment (in most of the cases), excluding inflammatory mediators. CONCLUSION: In most cases, resveratrol co-administration could sensitize cancerous cells to chemotherapy drugs through its oxidant, apoptosis, anti-inflammatory activities, etc. Nevertheless, suggesting the use of resveratrol during chemotherapy of colorectal cancer patients requires further clinical studies.

Effects of traditional Chinese medicine collaborative model (TCMCM) combined with adjuvant chemotherapy on IIIb and IIIc gastric cancer: a protocol for a randomized controlled trial.

BACKGROUND: Metastasis and/or recurrence can decrease the survival time of gastric cancer patients undergoing radical operation. Among them, those with stage IIIb and IIIc are especially at a high risk of metastasis and recurrence. The traditional Chinese medicine collaborative model (TCMCM) has been used in the treatment of cancer; however, its effects have not been systematically evaluated. This study is designed to evaluate whether TCMCM can decrease adverse effects after chemotherapy and reduce the recurrence and metastasis of stage IIIb and IIIc gastric cancer. METHODS/DESIGN: This prospective, multicenter, randomized, open-label trial will recruit 260 patients with stage IIIb and IIIc gastric cancer who undergo radical surgery for D2 lymphadenectomy. The patients will be randomly assigned to receive usual adjuvant chemotherapy and TCMCM (intervention group) in a 1:1 ratio. Patients in the intervention group will receive an oral traditional Chinese formula, auricular acupressure, and acupoint therapy. All participants will receive usual adjuvant chemotherapy. The primary outcome is a 3-year disease-free survival rate. Secondary outcomes include quality of life, side effects caused by chemotherapy, and safety-related measures. Assessments will be performed during the screening period, at 4 and 8 cycles after adjuvant chemotherapy, and 9, 12, 18, 24, 30, and 36 months after randomization. Adverse events will be recorded. In addition, biological samples will be collected for mechanism analysis. DISCUSSION: This will be the first clinical trial to evaluate the effects of TCMCM on disease-free survival (DFS) and quality of life in patients with stage IIIb and IIIc gastric cancer. Our results may be used to standardize TCMCM. We will also perform a larger-scale clinical trial in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT03607656 . Registered on 1 July 2018. The final protocol version is V1.1.

Can Elevated Pretreatment Serum Carcinoembryonic Antigen Levels Serve as a Potential Biomarker Guiding Adjuvant Chemotherapy in Rectal Cancer Patients With ypTis-3N0 After Neoadjuvant Radiotherapy and Surgery?

Survival benefit of adjuvant chemotherapy (ACT) remained controversial in patients with stage II/III rectal cancer (RC) who received neoadjuvant therapy and surgery. This study aimed to investigate the guiding role of elevated pretreatment serum carcinoembryonic antigen (CEA) levels for receiving ACT in yield pathological Tis-3N0 (ypTis-3N0) RC patients after neoadjuvant radiotherapy and surgery. Between 2004 and 2015, 10,973 RC patients with ypTis-3N0 who received neoadjuvant radiotherapy and radical surgery were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Compared with CEA-normal group, elevated-CEA patients had worse 5-year CSS rate (90.1 vs 83.5%). The 5-year CSS rates were 86.3 and 87.4% for ypTis-3N0M0 patients with or without ACT, respectively. Patients receiving ACT had a comparable 5-year CSS rate compared to those who did not regardless of CEA levels in ypTis-3N0M0 RC patients (CEA elevation group: 76.4 vs. 83.5%, P = 0.305; CEA normal group: 90.0 vs. 90.1%, P = 0.943). Intriguingly, ypT3N0M0 RC patients with elevated CEA levels may benefit from ACT (5-year CSS: 69.1 vs. 82.9%, P = 0.045), while those with normal CEA levels did not (5-year CSS: 89.3 vs. 89.3%, P = 0.885). Multivariate Cox analysis demonstrated that ACT tended to be a protective factor in elevated-CEA ypT3N0M0 RC patients (HR = 0.633, 95% CI = 0.344-1.164, P = 0.141), while ACT was not associated with improved CSS in normal-CEA ypT3N0M0 RC patients (HR = 1.035, 95% CI = 0.487-2.202, P = 0.928). Elevated pretreatment serum CEA levels may serve as a promising biomarker guiding ACT in rectal cancer patients with ypT3N0M0.

Polymorphisms in lncRNA PTENP1 and the Risk of Gastric Cancer in a Chinese Population.

Long noncoding RNA (lncRNA) phosphatase and tensin homolog pseudogene 1 (PTENP1) is significantly downregulated in gastric cancer (GC), playing critical roles in GC progression. However, the association between PTENP1 genetic variants and GC risk has not yet been reported. Using TaqMan technology, three lncRNA PTENP1 tag single nucleotide polymorphisms (tagSNPs) (rs7853346 C>G, rs865005 C>T, and rs10971638 G>A) were genotyped in 768 GC patients and 768 cancer-free controls in a Chinese population. We found that subjects with rs7853346 G allele had a remarkably decreased risk of GC, compared with those carrying C allele (P = 0.011 in an additive model, P = 0.033 after Bonferroni's correction). The further stratified analyses showed that the link between variant genotypes of rs7853346 and decreased GC risk was more obvious in older subjects (≥60 years), nonsmokers, nondrinkers, and subjects without family history of GC. We also found that relative PTENP1 mRNA expression levels were higher in rs7853346 CG/GG genotype carriers than those with common genotype in both GC and normal tissues (P < 0.05). Besides, bioinformatics analyses revealed that rs7853346 may change the local folding structure and alter the target microRNAs (miRNAs) of PTENP1. In conclusion, our results suggested that lncRNA PTENP1 polymorphism rs7853346 may predict GC susceptibility.

Functional Genetic Variants in SPHK1 Affect Susceptibility to Gastric Cancer in a Chinese Population.

BACKGROUND: An escalating number of studies have provided identified evidence that sphingosine kinase 1 (SPHK1) plays an essential role in carcinogenesis. This present study was devised to seek the possible correlation of two tag single-nucleotide polymorphisms (SNPs) in SPHK1 (rs3744037 T>C, rs346801 C>T) with the susceptibility to gastric cancer (GC). METHODS: This present case-control study was comprised of 710 patients with GC and 710 gender- and age-matched cancer-free individuals. The genotypes of the individuals were acquired by the TaqMan-MGB method. SPHK1 mRNA level was examined in 60 paired cancerous and noncancerous tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Our results suggested that the variant genotype T allele of SPHK1 rs346801 increased the GC risk in the study population [CT vs. CC, odds ratio (OR) = 1.385, 95% confidence interval (CI) = 1.096 - 1.751; TT vs. CC, OR = 2.502, 95% CI = 1.078 - 5.806; CT+TT vs. CC, OR = 1.434, 95% CI = 1.140 - 1.804]. Furthermore, in stratified analyses, rs346801 variant genotypes were associated with a conspicuous risk of GC in younger individuals (< 62 years), females, non-smokers, and individuals from rural areas. In addition, the carriers with variant genotype CT, TT, and CT+TT were observed to possess the higher SPHK1 messenger RNA levels than those with CC genotype in GC specimens. CONCLUSIONS: These results strongly demonstrated that the SPHK1 rs346801 C>T polymorphism may contribute to the susceptibility to gastric cancer in Chinese population and affect the expression of SPHK1 and, therefore, may act as a novel biomarker for predicting gastric cancer.

Identification of a synonymous variant in TRIM59 gene for gastric cancer risk in a Chinese population.

Tripartite motif 59 (TRIM59) is a novel oncogenic driver in gastric cancer (GC) that is implicated in disease progression as well as dismal survival. Genetic variants in peculiar gene are likely candidates for conferring hereditary susceptibility. The role of TRIM59 polymorphism in predicting the risk of malignant diseases and its relevance to TRIM59 expression have not been discussed. Using a HapMap tagSNPs approach, we screened three tag TRIM59 single nucleotide polymorphisms (SNPs) (rs1141023G>A, rs7629A>G, rs11706810T>C) which were genotyped in 602 GC patients and 868 healthy controls. Our study provided convincing result that carries of variant rs1141023A allele markedly increased GC risk (P=0.006). In comparison with the GG homozygotes, the variant GA heterozygotes demonstrated 1.50-fold elevated risk of GC (p=0.014, 95% confidence interval [CI] = 1.09-2.08). Subjects who carried the (GA+AA) genotypes of rs1141023 were associated with remarkable increased GC risk compared with the common genotype (P = 0.013, adjusted OR = 1.50, 95% CI = 1.09-2.05). Further stratified analyses displayed that the relationship between mutant genotype of rs1141023 and GC risk was more profound in male individuals. Intriguingly, there is no significant distinction of TRIM59 mRNA expression between rs1141023GA genotype and GG genotype in 44 normal gastric tissues. Taken together, our results suggest that rs1141023 polymorphism contributes to increased predisposition to GC and thus may be responsible for predicting early GC.

Tag SNPs of long non-coding RNA TINCR affect the genetic susceptibility to gastric cancer in a Chinese population.

Tissue differentiation-inducing non-protein coding RNA (TINCR) is required for normal epidermal differentiation. TINCR is also strongly overexpressed in human gastric cancer (GC) and contributes to carcinogenesis and tumor progression. However, the association between TINCR polymorphisms and the risk of any diseases, such as GC, remains unknown. In the present study, the tag single nucleotide polymorphisms rs8113645, rs2288947, rs8105637, and rs12610531 were analyzed in 602 patients with GC and 602 age- and sex-matched controls. Polymorphisms were genotyped using TaqMan technology. Carriers of variant rs8113645 and rs2288947 alleles indicated reduced risks of GC (p = 0.003 and 0.037, respectively). A allele genotypes of rs8113645 and G allele genotypes of rs2288947 (rs8113645 GA and AA; rs2288947 AG and GG) were also significantly associated with decreased GC risk (p < 0.05). Stratification analysis displayed that the correlations between GC risk and variant genotypes of both rs8113645 and rs2288947were more evident in younger individuals, men, nonsmokers, and individuals from rural areas. We also demonstrated that rs8113645 GA+AA genotype carriers had lower TINCR mRNA expression levels compared with common genotype in both normal and GC tissues (p < 0.05). These results suggest that long non-coding RNA TINCR polymorphisms may be implicated in GC development.

Association analysis of DACT1 genetic variants and gastric cancer risk in a Chinese Han population: a case-control study.

PURPOSE: Disheveled-binding antagonist of beta-catenin 1 (DACT1) is involved in tumorigenesis through influencing cell apoptosis and proliferation. We aimed to investigate the effect of three tag single-nucleotide polymorphisms (SNPs) in DACT1 (rs863091 C>T, rs17832998 C>T, and rs167481 C>T) on the occurrence of gastric cancer (GC), their association with specific clinical characteristics, and consideration of the functional relevance of GC-related SNPs. SUBJECTS AND METHODS: In this hospital-based case-control study, the genotypes were acquired using the TaqMan-MGB method consisting of 602 cases and 602 controls. DACT1 messenger RNA level was evaluated in 76 paired tumoral and normal tissues using quantitative reverse transcription-polymerase chain reaction. Logistic regression was used to evaluate the associations among the DACT1 SNPs and GC. RESULTS: We found a significant association between the variant genotypes of rs863091 and decreased risk of GC (TT vs CC: P=0.009, adjusted odds ratio =0.34, 95% confidence interval =0.15-0.77; CT + TT vs CC: P=0.030, adjusted odds ratio =0.74, 95% confidence interval =0.57-0.97). In further stratified analyses, rs863091 variant genotypes were associated with a reduced risk of GC in younger individuals (<60 years) and males. No overall significant association with GC risk was observed in SNP rs17832998 or rs167481. Additionally, we assessed DACT1 messenger RNA levels in GC and found that DACT1 expressions of individuals carrying CT and TT genotypes were much higher than those with CC genotype. CONCLUSION: Our findings suggest that the DACT1 rs863091 C>T polymorphism may be associated with a decreased risk of GC in the Chinese Han population and influence DACT1 expression.