Journal of Cancer Research and Clinical Oncology最新文献

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is considered a "cold" tumor because the tumor immune microenvironment (TIME) exhibits poor intratumoral T-cell infiltration. This study aimed to identify the marker genes associated with induction of cold TIME in PDAC cells.

Methods: We orthotopically transplanted 10 primary cultures of PDAC derived from KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice into immunocompetent mice and evaluated TIME by immunohistochemistry (IHC) staining of CD8. We divided primary cultures into two groups: cold TIME group with low CD8⁺ T-cell infiltration and a hot TIME group with high infiltration. RNA sequencing was performed to identify specific genes in the cold TIME group, and single-cell RNA sequencing (scRNA-seq) data was used for validation. IHC was performed to evaluate expressions in human PDAC samples.

Results: We identified six genes specific in PDAC cells to the cold TIME group by RNA sequencing; these were defined as "cold tumor induction-related genes". Human PDAC scRNA-seq data revealed that cold tumor induction-related genes were significantly and negatively correlated with the number of CD8⁺ T-cells (p = 0.0341). These genes included protocadherin 7 (PCDH7). High expression of PCDH7 significantly and negatively correlated with the number of CD8⁺ T-cells in scRNA-seq (p = 0.0474) and IHC (p = 0.0110) data using human PDAC samples. PCDH7 was an independent factor for poor prognosis in PDAC (overall survival: hazard ratio = 2.07, p = 0.0367).

Conclusion: PCDH7 is a prognostic marker associated with CD8⁺ T-cell infiltration for PDAC patients.

Background: The cell division cycle associated 4 (CDCA4) plays a crucial role in various biological processes and is implicated in the progression of several tumors, however, the mechanisms by which it operates in bladder cancer remain unclear.

Methods: Utilizing data from the TCGA and GEO datasets of bladder cancer patients, we analyzed the expression of CDCA4 and its prognostic significance. We then constructed stable overexpression and knockdown bladder cancer cell lines to investigate the effects of CDCA4 on cell proliferation, migration, and invasion in vitro, employing CCK-8, colony formation, transwell, and wound healing assays. Additionally, we validated the potential downstream pathways of CDCA4 through data analysis and western blot assays.

Results: Our study found that CDCA4 expression is elevated in bladder cancer cells and correlates with poor prognosis in patients. Inhibition of CDCA4 expression reduces the proliferation, migration, and invasion of bladder cancer cells, as well as inhibit the epithelial-mesenchymal transition (EMT) process. Conversely, promoting CDCA4 expression enhances the malignancy of bladder cancer cells. Investigation into the mechanism of CDCA4 revealed that it promotes bladder cancer progression by activating the JAK/STAT signaling pathway, and the JAK inhibitor AG490 can reverse the promoting effects of CDCA4.

Conclusion: Our findings suggest that CDCA4 enhances the proliferation, migration, and invasion of bladder cancer cells by positively regulating the JAK/STAT signaling pathway, indicating that CDCA4 may serve as a novel molecular target for bladder cancer treatment.

Purpose: Nivolumab plus ipilimumab (Nivo-Ipi) combination therapy is an effective first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its effectiveness and feasibility in elderly patients (aged ≥ 75 years) remain unclear. This study aimed to investigate the efficacy and safety of first-line Nivo-Ipi therapy in elderly patients with NSCLC.

Methods: This retrospective study included 57 patients with NSCLC (52 men and 5 women), aged ≥ 75 years (range: 75-86) who received first-line Nivo-Ipi therapy from December 2020 to November 2022 at four institutes in Japan. Patient characteristics, therapeutic efficacy, and the incidence and severity of adverse events (AE) were assessed.

Results: The overall response rate was 42.1%, the disease control rate was 73.6%, the median progression-free survival (PFS) was 7.1 months, and the median overall survival (OS) was 14.1 months. Common Grade ≥ 3 AEs included pneumonitis, elevated aspartate transaminase, elevated alanine transaminase, adrenal insufficiency, and colitis. No treatment-related deaths were reported. PFS and OS were longer in patients who experienced treatment-related AEs. Patients with and without AEs had a median PFS of 11.7 and 2.8 months, respectively. Similarly, the median OS of patients with and without AEs was 20.4 and 9.0 months, respectively.

Conclusion: First-line Nivo-Ipi therapy is effective in elderly patients with NSCLC. Although there was an increased incidence of pneumonitis, the treatment was manageable and presented as a viable treatment option. Notably, the occurrence of treatment-related AEs was associated with improved clinical outcomes, suggesting a potential prognostic value of AEs in this population.

Purpose: The primary objectives of this trial were aimed at exploring the pharmacokinetic profiles and the human bioequivalence of an intravenous liposomal injection of doxorubicin hydrochloride in comparison with a reference formulation in Chinese patients diagnosed with metastatic breast cancer.

Methods: To achieve these goals, the trial employed a randomized, open-label, two-formulation crossover dosing strategy among Chinese patients with metastatic breast cancer. Pharmacokinetic (PK) evaluation was conducted through the collection of blood samples, and the liquid chromatography tandem mass spectrometry (LC/MS/MS) method was leveraged to quantify plasma concentrations of both liposome-encapsulated doxorubicin and non-encapsulated doxorubicin in patients. Throughout the trial, all adverse events observed in the patients were meticulously assessed.

Results: The results indicated that the maximum concentration (Cmax), AUC from time zero to the last measurable concentration (AUC_0-t), and AUC extrapolated to infinity (AUC_0-∞) of in vivo non-encapsulated doxorubicin after administration of both formulations fell within the 80.00%-125.00% range at a 90% confidence interval.

Conclusion: These findings strongly indicated that the tested formulations were bioequivalent to the reference formulation. The results also demonstrated that both formulations were well-tolerated, further establishing their safety profile in the context of metastatic breast cancer treatment.

Trial registration: Chinadrugtrials.org.cn Identifier: CTR20200878.

Purpose: Immune checkpoint blockades (ICBs) are promising, however they do not fit all types of tumor, such as those lack of tumor antigens. Induction of potent anti-tumor T cell immunity is critical for cancer therapy. In this study, we investigated the efficacy of immunotherapy via the immunogenic cell death (ICD) dying tumor cells in mouse models of lung metastasis and tumorigenesis.

Methods: ICD was induced by short exposure to lethal dose of chemotherapeutic drug doxorubicin (Dox), which initiated an irreversible ICD program in tumor cells. We immunized mice with ICD dying tumor cells in prevention, therapy in lung metastasis models, and Gprc5a-knockout (ko) model of lung tumorigenesis. T cells and macrophages isolated from lymph nodes or tumor tissues were analyzed by flow cytometry. Cytokines were analyzed by ELISA or Q-PCR analysis.

Results: Immunization with these live but ICD dying tumor cells induced potent tumor-specific anti-tumor T cell immunity, which not only protected host from challenge by these tumor cells in prevention and therapy in mouse model of lung metastasis, but also prevented tumors development in Gprc5a-ko mouse model of lung tumorigenesis. The lymphocytes from lymph nodes and tumor tissues exhibited greatly enhanced activities of Th1 cells and M1 macrophages.

Conclusion: Immunization with the ICD dying tumor cells evokes potent tumor-specific T cell immunity, which provides a novel approach for cancer immunotherapy.

Purpose: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The Fat mass and obesity-associated protein (FTO), a genetic variant associated with obesity, significantly impact the energetic metabolism of mechanical tumors. However, research on the function of FTO in CRC is scarce.

Methods: Bioinformatics analysis of TCGA and UALCAN databases was conducted to examine FTO expression in CRC. Immunohistochemistry was used to assess FTO and PKM2 protein expression in clinical specimens. In vitro experiments utilized five human colon cancer cell lines and a normal colon epithelial cell line, with Western blotting and RT-PCR for protein and mRNA quantification, respectively, and lentiviral transfection to modulate FTO expression. Cellular behaviors such as proliferation, migration, invasion, and apoptosis were evaluated using various assays. Immunofluorescence and Seahorse Xfe96 metabolic analysis were employed to study PKM2 expression changes and glycolytic stress. The effects of PKM2 inhibition by shikonin on cell viability and glycolytic activity were assessed using CCK-8 assay and Seahorse analysis.

Results: An upregulation of FTO was observed in colon cancer through data mining and analysis of pathological specimens. Besides, we discovered that the impact of FTO on colon cancer glycolysis has significant implications for colon proliferation, invasion, and metastasis. The protein expression of PKM2 and the intensity of fluorescence staining in the nucleus of PKM2 were detected to be increased in colon carcinoma cells with over-expression of FTO.

Conclusion: FTO plays a significant role in CRC progression by regulating PKM2 and promoting glycolysis.

Purpose: To evaluate the added value of additional ⁶⁸Ga-FAPI PET/CT following CT for primary staging, detection of postoperative recurrence, and management of gastric cancer patients.

Methods: We retrospectively included patients with gastric cancers who underwent contrast-enhanced computed tomography (ceCT), followed by ⁶⁸Ga-FAPI PET/CT within 30 days. ⁶⁸Ga-FAPI PET/CT was performed for initial staging or detection of postoperative recurrence. Two nuclear medicine physicians and a radiologist independently decided on imaging-based staging. Pre-⁶⁸Ga-FAPI PET/CT treatment decisions were made by a simulated tumor board and post-⁶⁸Ga-FAPI PET/CT decisions were extracted from medical records. We evaluated the impact of ⁶⁸Ga-FAPI PET/CT with inconsistent new findings based on the initial findings from ceCT and the resulting changes in treatment strategies.

Results: We included 112 patients, 84 for initial staging and 28 for detection of postoperative recurrence. Compared to CT, 29 new findings in 24 patients were diagnosed as, or ruled out, cancer involvement on ⁶⁸Ga-FAPI PET/CT. Among the 112 patients, 21 patients (18.8%) experienced changes in stage or postoperative recurrence. Among patients for initial staging, 14 had stage changes, with 10 being upstaged and 4 being downstaged. Among patients for detection of postoperative recurrence, 7 more patients were diagnosed with tumor recurrence. New findings of ⁶⁸Ga-FAPI PET/CT led to treatment change in 20/112 (17.9%) patients, which was deemed of major change in 19 patients and minor change in 1 patient.

Conclusions: ⁶⁸Ga-FAPI PET/CT is valuable for precise staging and detection of postoperative recurrence of gastric cancers, and has the potential to influence management.