Anticancer research最新文献

Background/aim: Recently, we demonstrated that cancer dormancy is initiated within the lymphovascular tumor embolus and consists of decreased proliferation and lower mammalian target of rapamycin (mTOR) activity. In the present study, we investigated other intersecting metabolism-signaling pathways that may ultimately determine whether the lymphovascular tumor embolus remains dormant or undergoes cell death.

Materials and methods: The present study exploited a singular patient-derived xenograft (PDX) of inflammatory breast cancer (Mary-X) that spontaneously forms high density spheroids, the in vitro equivalent of emboli. The AMPK metabolic checkpoint pathway, the mTOR nutrient-responsive cell growth pathway, the P13K/Akt intracellular quiescence regulating pathway, and the calpain-mediated E-cadherin proteolytic pathway responsible for spontaneous spheroid-genesis were also investigated, to determine their relative contributions to dormancy.

Results: The levels of phosphorylated AMPK proteins (AMPKα and β subunits) decreased gradually with the formation of MARY-X spheroids in vitro. Rapamycin down-regulated mTOR activity, yet dormancy persisted. LY294002, a PI3K/Akt inhibitor, completely abolished mTOR and induced spheroid disadherence and apoptosis. Compound C (AMPK inhibitor) up-regulated mTOR and induced spheroid disadherence and apoptosis. Increasing cellular metabolism led to cell death, even in enriched medium, whereas growing the spheroids in serum-free media (starvation) did not result in further mTOR inhibition, and dormancy was maintained.

Conclusion: An increase in our understanding of dormancy from the standpoint of internal signaling pathways might ultimately provide clues to the external stimuli (starvation, hypoxia or other not yet understood phenomena) that act through these pathways to maintain or disrupt dormancy.

Background/aim: Methotrexate (MTX) resistance in osteosarcoma results in a very poor patient prognosis. We previously reported that super MTX-resistant osteosarcoma (143B-MTX^SR) cells, selected from parental 143B osteosarcoma (143B-P) cells by culturing them with increasing concentrations of MTX, exhibited reduced malignancy, despite the over-expression of oncogenes. The present study explored the mechanism of reduced malignancy in the super MTX-resistant osteosarcoma cells.

Materials and methods: Previously selected 143B-MTX^SR cells which are 5,500 times more MTX resistant than parental cells, were used for this study. The status of methylated histone H3K9me3 and H3K27me3 marks was examined with western immunoblotting and compared between 143B-MTX^SR and parental 143B-P cells.

Results: Histone H3K9me3 and H3K27me3 marks were over-expressed in 143B-MTX^SR compared to 143B-P (p<0.05, p<0.01, respectively).

Conclusion: Over-expression of histone H3K9me3 and H3K27me3 marks may be related to super-MTX resistance and to the loss of malignancy of super MTX-resistant osteosarcoma cells due to the fundamental relationship of methylation and cancer.

Background/aim: Elevated blood fibronectin (FN) levels have been observed in various cancers; however, their significance remains controversial. Herein, we measured the levels of sialyl-fibronectin (S-FN), a type of FN secreted by tumor cells, and investigated whether blood S-FN secretion is associated with recurrent metastasis and epithelial-mesenchymal transition (EMT).

Patients and methods: An ELISA system recognizing S-FN was constructed, and the amount of S-FN in blood samples from 63 patients with thyroid carcinoma was measured. The relationship between S-FN secretion and clinical prognosis was also examined. Vimentin immunostaining was performed to identify the mesenchymal status of the cells during EMT.

Results: After 12 years of observation, 17/63 patients had recurrent metastases, including nine cases of lymph node recurrence (LNR) and eight cases of remote metastasis (RM). LNR occurred in 7/39 (17.9%) of S-FN-negative cases, where 4/7 (57.1%) had two or more repeat recurrences. In S-FN-positive cases, LNR was observed in 2/24 cases (8.3%), and no repeat recurrence was observed. For RM, 6/39 (15.4%) patients were S-FN-negative, of which 5/6 (83.3%) had progressive disease even during treatment at metastasis. Of the S-FN-positive cases, RM was observed in 2/24 (8.3%) patients; progressive disease was observed in 1/2 (50.0%) patients. In 9/11 S-FN-negative recurrent metastasis cases (81.8%) and 2/4 S-FN-positive cases (50.0%), many vimentin-positive, FN-secreting cells were found in the interstitial tissue around the tumor.

Conclusion: S-FN-negative thyroid cancer has a poor prognosis because of the progression of EMT associated with increased paracrine FN levels in the stroma.

Background/aim: Many glioma patients struggle to return to work after surgery because of higher brain dysfunction. Although the right frontal lobe has historically been considered functionally silent, reports of performing awake surgery to evaluate higher brain functions in patients with tumors in this area have increased. We present two cases of patients who underwent awake surgery for malignant glioma in the right frontal lobe to preserve emotional recognition and facilitate an early return to work.

Case report: Case 1 was a 48-year-old right-handed woman employed as a nursery school teacher and case 2 was a 21-year-old right-handed man employed in sales. Both had contrast-enhancing right frontal lobe tumors exhibiting high signal intensity on fluid attenuated inversion recovery imaging and underwent awake surgery. During the operation, cortical mapping was performed using the Reading the Mind in the Eyes, calculation, and motor tasks. Resection of sites involved in motor and emotional recognition functions was avoided. In case 1, all regions of high signal intensity were completely resected; in case 2, all regions exhibiting enhancement were resected. Both patients were discharged home without neurological deficits and returned to work within 21 days after surgery.

Conclusion: It may be important to focus not only on overall survival and progression-free survival in glioma patients, but also on factors associated with life satisfaction, such as time to return to work after surgery and time until work becomes difficult. Awake surgery aimed at preserving higher brain functions is useful and may also improve life satisfaction.

Background/aim: To investigate the significance of the timing of chemoradiotherapy together with clinical and laboratory features in newly diagnosed glioblastoma.

Patients and methods: Clinical and laboratory parameters of 209 patients with glioblastoma potentially influencing overall (OS) and progression-free (PFS) survival were analyzed in univariable and multivariable models.

Results: On univariable analyses, Karnofsky performance status (p<0.001), recursive partitioning analysis (RPA) class (p<0.001), O⁶-methylguanine-DNA methyltransferase (MGMT)-status (p<0.001), extent of resection (p<0.001), radiotherapy dose (p=0.01), and the number of adjuvant temozolomide (TMZ) cycles (p<0.001) were significantly associated with OS. Additionally, MGMT-status (p<0.001), extent of resection (p=0.03), surgical site infections (p=0.02), and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with PFS. Multivariable analysis identified radiotherapy dose as the only independent predictor (p=0.049) of OS. MGMT-status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were independent predictors of PFS.

Conclusion: The timing of chemoradiotherapy did not play a prognostic role. For OS, the radiotherapy dose, and for PFS, MGMT-status and the number of adjuvant TMZ cycles were identified as independent prognostic factors.

Background/aim: In gastric cancer (GCa) tissues, mRNA expression of matrix metalloproteinase-8 (MMP-8) is notably reduced compared to healthy tissues. Furthermore, abnormally low or elevated serum levels of MMP-8 have been linked to a significantly poor prognosis. The involvement of MMP-8 genotypes in susceptibility to GCa remains underexplored. We aimed to assess the influence of MMP-8 genotypes on GCa susceptibility and their potential interactions with smoking, alcohol consumption, and Helicobacter pylori (H. pylori) infection.

Patients and methods: The study utilized polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) to analyze MMP-8 rs11225395, rs34009635, and rs35866072 genotypes in 161 GCa patients and 483 controls.

Results: No statistically significant difference was detected in the distribution of genotypic (p for trend=0.3635) or allelic (p=0.1954) frequencies of MMP-8 rs11225395. Under a dominant model, combined CT+TT genotypes showed no association with GCa risk [odds ratio (OR)=0.77, 95% confidence interval (95%CI)=0.54-1.10, p=0.1852]. Similarly, no association was observed for MMP-8 rs34009635 or rs35866072. Importantly, individuals with the MMP-8 rs11225395 CC genotype demonstrated a significant increase in GCa risk when exposed to smoking (OR=4.04, 95%CI=2.28-7.16, p=0.0001), alcohol consumption (OR=2.83, 95%CI=1.64-4.89, p=0.0002), and H. pylori infection (OR=3.53, 95%CI=2.12-5.90, p=0.0001).

Conclusion: The findings indicate that individuals carrying the MMP-8 rs11225395 CC genotype have increased susceptibility to GCa, especially when combined with risk factors, such as smoking, alcohol consumption, and H. pylori infection. These results suggest that MMP-8 genotype-based preventive strategies, including lifestyle alterations and targeted infection treatments, may be valuable in mitigating GCa development.

Background/aim: Lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) accounts for the majority of non-small cell lung cancer (NSCLC), and overexpression of programmed death ligand 1 (PD-L1) in these cells is known to induce tumor immune evasion or drug resistance. However, detailed studies are needed to determine whether microRNAs (miRNAs) that reduce PD-L1 expression can suppress drug resistance in NSCLC.

Materials and methods: Kaplan Meier plotter and Receiver Operating Characteristic plotter were used to determine the effect of specific miRNAs on survival and chemotherapy response in NSCLC patients. Cell viability, colony formation and invasion assays, and qPCR analyses were also performed.

Results: The expression of miRNA-140-3p (miR-140-3p) was lower in LUAD patients, compared to the normal group, and low expression of miR-140-3p was associated with poor survival of LUAD patients, but not in LUSC. The miR-140-3p mimic inhibited proliferation, colony formation, and invasion of LUAD cells. Interestingly, the expression of miR-140-3p was significantly lower in the group of LUAD patients who did not respond to docetaxel. In LUAD cells, combined treatment with miR-140-3p and docetaxel significantly reduced cell viability as well as the expression of ABCG2 and MVP, genes associated with drug resistance, compared to either treatment alone. Additionally, combined injection of miR-140-3p mimic and docetaxel significantly inhibited tumor growth compared to treatment with docetaxel alone.

Conclusion: These results suggest that the high expression of miR-140-3p in LUAD is correlated with good patient prognosis and may contribute to the treatment of LUAD, especially by increasing responsiveness to docetaxel.

Background/aim: Tubular adenomas of the colon (TA) are neoplastic polyps composed of dysplastic tube-like crypts. Nondysplastic crypts, mostly in asymmetric branching have been previously reported, both beneath and bordering TA. In the present article, intercalated nondysplastic crypts (INDC) amidst dysplastic crypts in TA are showcased.

Patients and methods: The occurrence of INDC was recorded in 139 TA.

Results: Out of the 139 TA, 31% exhibited INDC; of these, 58% were in asymmetric branching (INDCAB), 35% were single intercalated crypts without branching (INDSNB), and 7% were in symmetric branching (INDCSB). Luminal dysplasia occurred in 53% out of the 43 TA: in 37% TA with INDCAB, in 16% TA with INDSNB, but in none of the TA with INDCSB. Thus, INDCAB predominated.

Conclusion: The finding of INDC in TA domain contrasts with the infrequency of INDCSB and with the absence of INDCAB in the normal colorectal mucosa. Hence, INDC emerge as integral components in TA. Since only 1 or 2 sections were available per TA, the total number of INDC in the entire TA is likely higher. INDC in TA may be remnants of acquired nondysplastic mucosal cores of abnormal cryptogenesis that were subsequently replaced by top-down growing dysplastic epithelium. The present and previous findings support the concept of field cancerization in the human colorectum.

Background/aim: Granzyme B (GZMB) is mainly produced by natural killer (NK) cells and activated CD8-positive T cells to induce tumor cell apoptosis. We analyzed the significance of GZMB expression in gastric cancer (GC) tissues from patients with pathological (p)Stage II/III GC after curative resection.

Patients and methods: Patients with pStage II/III GC who received curative resection (n=253) were included and the expression levels of GZMB in GC tissues and in the adjacent normal mucosa were measured using quantitative real-time polymerase chain reaction. The expression levels in GC tissues and clinicopathological features and overall survival (OS) were compared in these patients.

Results: GZMB expression levels were significantly higher in GC tissues than in the adjacent normal mucosa. GZMB expression levels in GC tissues were not associated with any clinicopathological features. The 5-year OS rate in the high-GZMB expression group was significantly better than that in the low-expression group (5-year survival rate 72.0% vs. 55.7%; p=0.009). Furthermore, on multivariate analysis, high-GZMB expression was an independent factor for better OS (hazard ratio=0.652; 95% confidence interval=0.432-0.987; p=0.043).

Conclusion: In patients with locally advanced GC after curative resection, GZMB expression in GC tissue may be a useful prognostic marker.