Abstract Resistance to epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure and cancer recurrence in non-small cell lung cancer (NSCLC). Approximately 30% of patients with EGFR-activating mutations exhibit primary resistance to EGFR–TKIs. However, the potential mechanisms of primary resistance to EGFR–TKIs remain poorly understood. Recent studies have shown that increased expression of programmed death ligand-1 (PD-L1) is associated with EGFR–TKIs resistance. Therefore, the present study aimed to investigate the mechanism of PD-L1 in primary resistance to EGFR–TKIs in EGFR-mutant lung adenocarcinoma (LUAD) cells. We found that PD-L1 was associated with poor prognosis in patients with EGFR-mutant LUAD, while the combination of EGFR–TKIs with chemotherapy could improve its therapeutic efficacy. In vitro and in vivo experiments revealed that PD-L1 promoted the proliferation and autophagy and inhibited the apoptosis of LUAD cells. Mechanistic studies demonstrated that upregulation of PD-L1 was critical in inducing autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, which was beneficial for tumor progression and the development of gefitinib resistance. Furthermore, we found that gefitinib combined with pemetrexed could synergistically enhance antitumor efficacy in PD-L1-overexpression LUAD cells. Overall, our study demonstrated that PD-L1 contributed to primary resistance to EGFR–TKIs in EGFR-mutant LUAD cells, which may be mediated by inducing autophagy via the MAPK signaling pathway. These findings not only help improve the prognosis of patients with EGFR-mutant LUAD but also provide a reference for the research of other cancer types.
Mature T- and natural killer (NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T- and NK-cell lymphomas is 2.1 per 100,000 people, according to a US report[1][1]. Due to the heterogeneity, rarity, and diagnostic
Objective. Concurrent follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) (defined as FL/DLBCL) have been considered an important pathological feature in cell lymphoma. However, clinicopathological information and prognostic factors in these cases are scarce. The aim of this study was to construct a prediction index to compare with traditional prognostic models. Methods. Retrospectively enrolled, previously untreated FL/DLBCL ( ) patients, as well as those with pure FL 1–3a ( ), were assessed. De novo DLBCL ( ) were used as controls. Kaplan–Meier curves were plotted to compare the outcomes among the three groups. Multivariate analysis identified risk factors associated with overall survival (OS) in FL/DLBCL patients. A clinicopathological prognosis index (CPPI) was developed to predict OS based on the Cox proportional hazards model. Results. The outcomes of FL/DLBCL patients were intermediate between pure FL 1–3a and de novo DLBCL patients, with a 5-year PFS of 70%, 59%, and 48% ( ) and 5-year OS of 80%, 70% and 60% ( ), respectively. Cox regression analysis showed that the prognostic factors of OS for FL/DLBCL patients included FL grade, cell of origin, and Ann Arbor stage. A nomogram and clinicopathological prognostic index (CPPI) were developed to predict the OS for FL/DLBCL patients based on these factors. The area under the curve (AUC) of the CPPI for 3- and 5-year OS prediction was 0.782 and 0.860, respectively. This was superior to that of the International Prognostic Index (IPI), Follicular Lymphoma International Prognostic Index (FLIPI), and FLIPI2 in the 0.540–0.819 ( ) range. Conclusions. A valid OS estimation in FL/DLBCL patients, using the recommended CPPI, may be useful in routine clinical practice.
Rationale: A number of guanine nucleotide exchange factors (GEFs) including epithelial cell transforming factor ECT2 are believed to drive carcinogenesis through activating distinct oncogenic GTPases. Yet, whether GEF-independent activity of ECT2 also plays a role in tumorigenesis remains unclear. Methods: Immunohistochemical (IHC) staining, colony formation and xenograft assays were used to examine the role of ECT2 in breast carcinogenesis. Co-immunoprecipitation, immunofluorescent stainings, in vivo deubiquitination and in vitro deubiquitination experiments were performed to examine the physical and functional interaction between ECT2 and ubiquitin-specific protease USP7. High-throughput RNA sequencing, quantitative reverse transcription-PCR and Western blotting were employed to investigate the biological significance of the interplay between ECT2 and USP7. Results: We report that ECT2 plays a tumor-promoting role in breast cancer, and GEF activity-deficient ECT2 is able to alleviate ECT2 depletion associated growth defects in breast cancer cells. Mechanistically, we demonstrated that ECT2 physically interacts with ubiquitin-specific protease USP7 and functionally facilitates USP7 intermolecular self-association, -deubiquitination and -stabilization in a GEF activity-independent manner. USP7 in turn, deubiquitinates and stabilizes ECT2, resulting in a feedforward regulatory circuit that ultimately sustains the expression of oncogenic protein MDM2. Conclusion: Our study uncovers a GEF-independent role of ECT2 in promoting survival of breast cancer cells, provides a molecular insight for the reciprocal regulation of ECT2 and USP7, and supports the pursuit of ECT2/USP7 as potential targets for breast cancer intervention.
Vasculogenic mimicry (VM) is a nonangiogenesis-dependent pathway that promotes tumor growth and disease progression. Nodal signaling has several vital roles in both embryo development and cancer progression. However, the effects of Nodal signaling on VM formation in breast cancer and its underlying mechanisms are ill-defined. We analyzed the relationship between Nodal signaling and VM formation in one hundred human breast cancer cases and the results showed that the expression of Nodal was significantly correlated with VM formation, tumor metastasis, differentiation grade, TNM stage and poor prognosis. Furthermore, up-regulation of Nodal expression promoted VM formation of breast cancer cells in vitro and in vivo. Knockdown of Nodal expression restrained VM formation. In addition, Nodal induced EMT and up-regulated the expression of Slug, Snail and c-Myc. We found that blocking the Smad2/3 pathway by administering SB431542 inhibited VM formation in breast cancer cell lines and xenografts. Taken together, Nodal signaling through the Smad2/3 pathway up-regulated Slug, Snail and c-Myc to induce EMT, thereby promoting VM formation. Our study suggests that the Nodal signaling pathway may serve as a therapeutic target to inhibit VM formation and improve prognosis in breast cancer patients.
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA), as a rare primary hepatic tumor, is challenging to accurately assess in terms of the clinical outcomes and prognostic risk factors in patients. This study aimed to clarify the function of tertiary lymphoid structure (TLS) status in predicting the outcome of cHCC-CCA and to preliminarily explore the possible mechanism of TLS formation.
Although the role of tumor-infiltrating T cells in follicular lymphoma (FL) has been reported previously, the prognostic value of peripheral blood T lymphocyte subsets has not been systematically assessed. Thus, we aim to incorporate T-cell subsets with clinical features to develop a predictive model of clinical outcome.We retrospectively screened a total of 1,008 patients, including 252 newly diagnosed de novo FL patients with available peripheral blood T lymphocyte subsets who were randomized to different sets (177 in the training set and 75 in the internal validation set). A nomogram and a novel immune-clinical prognostic index (ICPI) were established according to multivariate Cox regression analysis for progression-free survival (PFS). The concordance index (C-index), Akaike's information criterion (AIC), and likelihood ratio chi-square were employed to compare the ICPI's discriminatory capability and homogeneity to that of FLIPI, FLIPI2, and PRIMA-PI. Additional external validation was performed using a dataset (n = 157) from other four centers.In the training set, multivariate analysis identified five independent prognostic factors (Stage III/IV disease, elevated lactate dehydrogenase (LDH), Hb <120g/L, CD4+ <30.7% and CD8+ >36.6%) for PFS. A novel ICPI was established according to the number of risk factors and stratify patients into 3 risk groups: high, intermediate, and low-risk with 4-5, 2-3, 0-1 risk factors respectively. The hazard ratios for patients in the high and intermediate-risk groups than those in the low-risk were 27.640 and 2.758. The ICPI could stratify patients into different risk groups both in the training set (P < 0.0001), internal validation set (P = 0.0039) and external validation set (P = 0.04). Moreover, in patients treated with RCHOP-like therapy, the ICPI was also predictive (P < 0.0001). In comparison to FLIPI, FLIPI2, and PRIMA-PI (C-index, 0.613-0.647), the ICPI offered adequate discrimination capability with C-index values of 0.679. Additionally, it exhibits good performance based on the lowest AIC and highest likelihood ratio chi-square score.The ICPI is a novel predictive model with improved prognostic performance for patients with de novo FL treated with R-CHOP/CHOP chemotherapy. It is capable to be used in routine practice and guides individualized precision therapy.
The data about the clinical features and outcomes of Chinese patients with follicular lymphoma (FL) are limited. Here, we conducted a retrospective study to explore the initial treatment strategies and clinical outcomes of Chinese patients with FL in the real world.This study included FL patients who were newly diagnosed in Tianjin Medical University Cancer Institute and Hospital from March 2002 to August 2020.A total of 926 FL patients were enrolled. The median age was 54 years old, and the majority of the Chinese FL patients had advanced-stage disease and Eastern Cooperative Oncology Group(ECOG) <1 but less frequently infiltrated bone marrow. After a median of 38-month follow-up, the 5-year progressive-free survival (PFS) and overall survival (OS) of grade1-3a were 57.8% and 88.7%, respectively, which both are similar to those reported in previous Chinese and Western studies. The co-existence at diagnosis of FL and diffuse large B-cell lymphoma (DLBCL) components (FL/DLBCL) was associated with poor outcomes. The FL grades and proportion of DLBCL component in FL/DLBCL did not have an impact on PFS and OS. The most common regimen with great efficacy and risk-benefit was RCHOP-like followed by R maintenance regimen. The 5-year cumulative hazard of histological transformation (HT) was 4.7% (95% CI, 3.5-5.9); median time to transformation was 23.5 months (range, 2-146 months) after diagnosis. Three-year survival following transformation was 55% (95% CI, 40-70). Patients with stage III-IV, elevated β2 microglobulin (β2-MG), and B symptoms seemed to be more prone to progress within 24 months of frontline therapy (POD24). The FLIPI-2 showed the highest specificity to predict POD24, reflecting the prediction of correctly classifying as low-risk patients, but the FLIPI had the highest sensitivity to predict the risk of progression for critical patients.We revealed the clinical characteristics and outcomes of FL patients in the real world in China, which may provide novel data on prognostic factors and primary treatment of FL, applicable to routine clinical practice.
Introduction: Intrahepatic cholangiocarcinoma (ICC) is one of the most highly heterogeneous malignant solid tumors; it is generally insensitive to clinical treatment and has a poor prognosis. Evidence suggests that abnormal neovascularization in the tumor microenvironment is an important cause of treatment resistance as well as recurrence and metastasis, but the key regulatory molecules are still largely unknown and should be identified. Method: We assessed the novel extracellular matrix protein (ECM) Sushi, von Willebrand factor type A, EGF and pentraxin containing 1 (SVEP1) expression pattern in the ICC by using immunohistochemistry. Multiplex immunofluorescence and Kaplan-Meier analysis were applied to explore the correlation between the low expression of SVEP1 and abnormal blood vessels and the clinical prognosis of ICC. Results: Our study showed that the expression of SVEP1 in most ICC samples was relatively lower than in the adjacent tissues. Statistical analysis suggested that patients with decreased SVEP1 expression always had shorter overall survival (OS) and disease-free survival (DFS). Moreover, the expression of SVEP1 was negatively correlated with the proportion of abnormal neovascularization in the tumor microenvironment of the ICC. Consistently, the key molecule of promoting vascular normalization, Ang-1, is positively correlated with the SVEP1 expression and prognosis in the ICC. In addition, the proportion of high Ki-67 expression was higher in the ICC samples with low SVEP1 expression, suggesting that the SVEP1 low expressed sample is in a malignant phenotype with high proliferation. Conclusion: This study reveals that SVEP1 is a promising prognostic biomarker for ICC and provides fresh insight into the role and potential new mechanism of abnormal neovascularization in ICC progression.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
