PDIA3 driven STAT3/PD-1 signaling promotes M2 TAM polarization and aggravates colorectal cancer progression.

OBJECTIVE: This inquiry endeavors to delineate the influence of PDIA3 on tumor-associated macrophages within the realm of colorectal malignancies, whilst elucidating the intrinsic biochemical pathways. METHOD: Leveraging bioinformatics, we scrutinized the symbiosis between PDIA3, STAT3, and CD274. A xenograft model in immunodeficient murine served to assess PDIA3's impact on colorectal carcinogenesis. Further, Western blot analysis quantified the protein expression of PDIA3, p-STAT3, PD-1, XBP-1, assorted enzymes, and IL-6. Moreover, in vitro assays gauged SW480 cellular dynamics inclusive of migration, invasive potential, and proliferation. RESULTS: Bioinformatics exploration exposed PDIA3's elevated presence in diverse cancers, with a marked expression in colorectal cancer, as per TCGA and GEO repositories. Correlative studies showed PDIA3 positively aligning with STAT3 and CD274, the latter also associated with monocyte-derived macrophages. Comparative analysis of colorectal neoplasms and normal colon samples unveiled heightened levels of PDIA3 markers which, when overexpressed in SW480 cells, escalated tumorigenicity and oncogenic behaviors, with a noted decrease upon PD-1 monoclonal antibody intervention. CONCLUSIONS: PDIA3 augments the M2 polarization of tumor-associated macrophages via modulation of the STAT3/PD-1 cascade, thus invigorating the tumorous proliferation and dissemination in colorectal cancer. Such revelations position PDIA3 as an auspicious target for PD-1 blockade therapeutics, offering a promising foundation for rectifying colorectal carcinoma.

The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients.

BACKGROUND: Cell division control protein 42 (CDC42) is involved in colorectal cancer (CRC) progression by modulating CD8+ T cell activation, immune escape, and direct oncogenetic biological processes. This study aimed to explore the correlation of blood CDC42 with disease risk, comorbidities, disease features, tumor markers, and prognosis among CRC patients. METHODS: CDC42 in peripheral blood mononuclear cells was detected by reverse transcription-quantitative polymerase chain reaction from 250 resectable CRC patients and 50 healthy controls (HCs). CDC42 was divided by quartiles, as well as high and low expressions in CRC patients for correlation and survival analysis. RESULTS: CDC42 was elevated in CRC patients vs. HCs (p < 0.001), which had a good ability to distinguish CRC patients from HCs with the area under the curve (95% confidence interval) of 0.889 (0.841-0.937). In CRC patients, CDC42 was not associated with demographics or comorbidities (all p > 0.05), while its higher quartile was linked to increased T stage (p < 0.001), N stage (p = 0.009), TNM stage (p < 0.001), abnormal carcinoembryonic antigen (p = 0.043), and adjuvant chemotherapy administration (p = 0.002). Higher CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p < 0.001) were related to worse disease-free survival (DFS); meanwhile, elevated CDC42 quartile (p = 0.002) and CDC42 high (vs. low) (p = 0.001) were also linked to poor overall survival (OS). Multivariate Cox's regression analysis presented that CDC42 quartile 3 and 4 (vs. quartile 1) independently predicted declined DFS and OS (all p < 0.05). CONCLUSION: Circulating CDC42 relates to higher disease risk, T, N, and TNM stage, abnormal tumor marker, and poor prognosis among CRC patients.

Multidisciplinary approach to the diagnosis and treatment of patients with potentially resectable colorectal cancer liver metastasis: results of a multicenter study.

BACKGROUND: This study sought to review colorectal cancer liver metastasis (CRLM) patients at multiple centers to analyze the factors affecting the success of conversion therapy in patients whose CRLM was initially evaluated as potentially resectable, to explore the effect of different treatment approaches on patient survival, and to provide a scientific reference for clinical treatment of CRLM. METHODS: Fifty patients whose CRLM was initially evaluated as potentially resectable at 3 large Chinese general hospitals were enrolled in this retrospective study. Statistical analyses were carried out on the general data and pathological characteristic data to examine the clinical efficacy of the treatment approaches. The factors affecting the success of conversion therapy were analyzed by logistic regression. Additionally, follow-up appointments were conducted to examine survival, and survival curves were plotted using the Kaplan-Meier estimator. The effect of different clinical and pathological characteristics on CRLM patients was analyzed. RESULTS: Seventeen patients achieved no evidence of disease (NED) status through surgical resection/ablation after undergoing conversion therapy. The multifactor analysis demonstrated that the number of liver metastases was the primary risk factor affecting the efficacy of conversion therapy (P<0.05). Survival analysis results showed statistically significant difference in overall survival (OS) between the NED group and the inconspicuous/progressive group (P<0.0001). Also, there was a statistically significant difference in the progression-free survival (PFS) between the NED group and the inconspicuous/progressive group (P<0.0001). Patients in the surgical resection group had better OS and PFS than those in the ablation group (P<0.0001 and P<0.01, respectively). The monofactor analysis demonstrated that the number and maximum diameter of liver metastases, serum Carcino-Embryonic Antigen (CEA) level, and BRAF V600E mutation status were factors affecting the OS of CRLM patients (P<0.05), of which BRAF V600E mutation was the primary determinant (P<0.05). CONCLUSIONS: Among the patients whose CRLM was initially evaluated as unresectable, those who underwent surgical resection of the primary lesions and liver metastases after receiving conversion therapy had the best prognosis. Thus, a thorough evaluation should be conducted to determine the effect of and survival factors affecting conversion therapy in the treatment of liver metastases.

Efficacy and safety of short duration radiotherapy combined with chemotherapy for advanced rectal cancer.

BACKGROUND: Radiotherapy or chemoradiotherapy is widely used for the treatment of rectal cancer preoperatively. Although the combination of radiotherapy and chemotherapy as an established preoperative neoadjuvant therapy shows high efficacy in the treatment of rectal cancer, some patients experience a response of poor tolerance and outcomes due to the long duration radiotherapy. The study compared short duration radiotherapy plus chemotherapy vs long duration radiotherapy plus chemotherapy for rectal cancer to determine whether short duration radiation treatment should be considered to diminish complications, reduce risk of recurrence and improve survival in patients with rectal cancer. AIM: To evaluate the efficacy and safety of short duration radiotherapy combined with chemotherapy for the treatment of advanced rectal cancer. METHODS: One hundred patients with stage IIIB or higher severe rectal cancer were selected as the study subjects at The First Affiliated Hospital of Hebei North University between December 2018 and December 2019. The patients were assigned to different groups based on the treatment regimens. Fifty patients who received preoperative short durations of radiotherapy plus chemotherapy were enrolled in an observation group and fifty patients who received conventional radiotherapy and chemotherapy were enrolled in a control group. Colonoscopic biopsy was performed for all patients with pathological diagnosis of rectal cancer. The expression of tumor-related factors such as RUNX3 and Ki-67 was quantitatively analyzed using immunohistochemistry in the tissues of the patients before and after treatment. Moreover, the duration of procedure, the amount of bleeding during the operation, the anus-conserving rate, the incidence of postoperative complications (wound infection, anastomotic leakage, postoperative intestinal obstruction, etc.) and postoperative pathology were compared between the two groups. The overall survival rate, recurrence rate and distant metastasis rate were also compared through postoperative reexamination and regular follow-up. RESULTS: There was no significant difference in the positive expression rate of RUNX3 and Ki-67 between the two groups before the treatment (P > 0.05). Compared with the pretreatment value, the positive rate of RUNX3 was increased and the positive rate of Ki-67 was decreased in both groups after the treatment (all P < 0.05). The incidence of leukopenia, thrombocytopenia, neutropenia and diarrhea were higher in the observation group than in the control group (all P < 0.05). There was no significant difference in the incidence of anemia, fatigue, neurotoxicity and nausea and vomiting between the two groups (all P > 0.05). No significant difference was observed in the duration of procedure, intraoperative bleeding, the anus-conserving rate and the incidence of postoperative complications between the two groups (P > 0.05). After 1 year of follow-up, the 1-yr survival rate was 80.0% in the observation group and 68.0% in the control group, the recurrence rate was 8.0% in the observation group and 10.0% in the control group, the distant metastasis rate was 6.0% in the observation group and 8.0% in the control group difference (all P < 0.05). CONCLUSION: Short duration radiotherapy combined with chemotherapy can improve the cure rate, prolong the survival time and reduce the incidence of complications in patients with advanced rectal cancer.