Cancer Biology & Therapy最新文献

Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.

Triple-negative breast cancer (TNBC) is a common malignant disease among females and severely threatens the health of women worldwide. Nowadays, circular RNAs (circRNAs) aroused our interest for their functions in human cancers, including TNBC. However, the mechanism of most circRNAs in the progression of TNBC remains unclear. We found a novel circRNA named circATP5C1, whose function in TNBC remains uncovered. Tissue microarray was used to analyze the association between the expression of circATP5C1 and the prognoses of TNBC patients. Gain-and loss-of-function experiments were performed to validate the biological functions of circATP5C1 in different TNBC cell lines. RNA-seq analyses were conducted to find out the target genes regulated by circATP5C1. RNA pull-down assay and mass spectrometry were used to select the proteins associated with circATP5C1. RNA FISH-immunofluorescence and RNA immunoprecipitation (RIP) were complemented to validate the interaction between circATP5C1 and its binding protein. CircATP5C1 was identified to have predictive function in prognosis of TNBC patients. CircATP5C1 advanced the progression of TNBC cells. Mechanistically, Colony stimulating factor 1 (CSF-1) is a vital downstream gene regulated by circATP5C1. The alteration of CSF-1 expression level was validated due to the interaction between circATP5C1 and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Rescue experiments demonstrated that circATP5C1 accelerates the progression of TNBC partly via binding with IGF2BP2 to increase the secretion of CSF-1. This study uncovers a novel mechanism of circATP5C1/IGF2BP2/CSF-1 pathway in regulating progression of TNBC.

CXC Chemokine receptor type 4 (CXCR4) is commonly considered a potential marker for cancer stem cells (CSCs). Dedifferentiated-type chordoma (DTC) cells derived from a patient with recurrent chordoma exhibit high CXCR4 expression and demonstrate increased resistance to chemotherapeutic drugs and ionizing radiation (IR) compared to the conventional-type chordoma cell line, U-CH1. However, the precise role of CXCR4 in the stemness and IR resistance of DTC remains unclear. Therefore, this study aims to elucidate the correlation between the expression of CXCR4 and stemness and radioresistance in chordoma. DTC cells expressing CXCR4 (CXCR4⁺ DTC cells), isolated by magnetic-activated cell sorting, exhibited increased self-renewal activity, tumorigenicity, and IR resistance, accompanied by elevated Sox2 expression. Knockdown of CXCR4 expression using short hairpin RNA, inhibition of CXCR4 signaling with AMD3100, and targeting of STAT3, a downstream effector of CXCR4, with WP1066 in DTC cells significantly diminished their self-renewal ability, tumorigenic potential, IR resistance, and Sox2 expression. Additionally, transfection with a small interfering Sox2 RNA suppressed self-renewal activity, tumorigenicity, and IR resistance in DTC cells, whereas overexpression of CXCR4 reversed these effects in U-CH1 cells. Furthermore, DTC cells infected with shCXCR4 exhibited substantial tumor suppression, and the combination of IR and AMD3100 significantly reduced DTC tumor growth in a mouse xenograft model. These findings underscore the functional significance of CXCR4 as a CSC marker, highlighting its potential as a therapeutic target for malignant chordomas.

Purpose: Abnormal expression of PINCH-1 has been observed in various types of human cancers. However, the clinical importance and mechanism underlying its role in head and neck squamous cell carcinoma (HNSCC) is yet to be fully elucidated.

Methods: This study evaluated the expression of PINCH-1 in HNSCC samples through immunohistochemical staining and Western blotting. AMC-HN-8, Cal27, and SCC7 cell lines were utilized for cellular function experiments, both in vivo and in vitro. CCK8, colony-formation assay, flow cytometry, wound-healing assay, and transwell assay were employed to investigate the effects of alterations in target proteins on the growth and metastasis of cancer cells. Mito-Tracker Deep Red FM was used to track mitochondrial morphology.

Results: PINCH-1 was found to be overexpressed in HNSCC and closely associated with lymph node metastasis and poor pathologic differentiation. Its upregulation promoted proliferation, inhibited apoptosis, and enhanced migration and invasion in HNSCC cells. It also promoted mitochondrial fission. We conducted a mechanism analysis, which showed that PINCH-1 knockdown inhibited mitochondrial fission by reducing the expression of DRP1. Furthermore, inhibition of mitochondrial fission could impede the proliferation and metastasis of HNSCC cells. Re-expression of DRP1 reversed the inhibitory effect of PINCH-1 knockdown on mitochondrial fission, cell proliferation, and metastasis in HNSCC cells.

Conclusions: PINCH-1 plays a critical oncogenic role in HNSCC by enhancing DRP1-mediated mitochondrial fission, which may serve as a novel therapeutic target for HNSCC.

Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients (N = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequent FIGO stages I or II (p = .002) and other than high-grade serous tumor subtypes (nonHGSCs) (p < .001), which was connected with lower KRAS transcript levels (p = .004). Patients with nonHGSC subtypes had less frequent TP53 mutations (p = .002). Carriers of TP53 variants disrupting the DNA binding loop had significantly longer platinum-free intervals than the rest (p = .037). Tumors bearing nonsense, frameshift, or splice site TP53 variants had a significantly lower TP53 transcript level, while those with missense variants had significantly higher levels than wild types (p < .001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and patients with co-mutated genes had poorer overall survival than others (p = .015). Protein levels of both genes significantly correlated with their respective transcripts (p = .028 and p = .001, respectively). Our study points to KRAS as a target for future therapy of nonHGSCs and reveals the prognostic value of TP53 variants in the DNA binding loop.

Osteosarcoma is the most common primary bone tumor in children and adolescents. Its pathogenesis is complex and poses difficulties in treatment. Autophagy is a cell biological process that plays a crucial role in the mechanistic study and treatment of osteosarcoma. The objective of this study is to evaluate the past research progress from 2007 to 2023 and visualize the key research directions through bibliometric methods. Relevant publications published from the start of 2007 to the end of 2023 were searched and screened in the Web of Science Core Collection. They were analyzed and visualized using CiteSpace and the Bibliometric online analysis platform in terms of country, institution, author, journal, cited references, and keywords. In total, 619 publications from 522 journals with 682 authors from 42 countries were screened. The country with the highest number of publications is China (n = 445, 71.890%), followed by the United States (n = 60, 9.693%). The research institution with the highest number of publications is Shanghai Jiao Tong University (n = 42, 6.785%). The author with the highest number of publications is Cai, Zhengdong (n = 7), while the most cited author is Mizushimma N (n = 93). Among many journals, AUTOPHAGY has the most citations (n = 342), while CANCER LETT shows the greatest centrality (Centrality = 0.05). "Autophagy" is the most cited keyword (n = 177), and the keyword with the largest burst intensity is "cancer cells" (Strength = 6.27), which lasted from 2011 to 2014. China is a major contributor to autophagy research in the field of osteosarcoma, followed by the United States. All publications are in high-quality journals. "Autophagy" is a hot research topic in this field.

CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

Ovarian cancer (OC) is a form of gynecological malignancy that is associated with worse patient outcomes than any other cancer of the female reproductive tract. Topoisomerase II α (TOP2A) is commonly regarded as an oncogene that is associated with malignant disease progression in a variety of cancers, its mechanistic functions in OC have yet to be firmly established. We explored the role of TOP2A in OC through online databases, clinical samples, in vitro and in vivo experiments. And initial analyses of public databases revealed high OC-related TOP2A expression in patient samples that was related to poorer prognosis. This was confirmed by clinical samples in which TOP2A expression was elevated in OC relative to healthy tissue. Kaplan-Meier analyses further suggested that higher TOP2A expression levels were correlated with worse prognosis in OC patients. In vitro, TOP2A knockdown resulted in the inhibition of OC cell proliferation, with cells entering G1 phase arrest and undergoing consequent apoptotic death. In rescue assays, TOP2A was confirmed to regulate cell proliferation and cell cycle through AKT/mTOR pathway activity. Mouse model experiments further affirmed the key role that TOP2A plays as a driver of OC cell proliferation. These data provide strong evidence supporting TOP2A as an oncogenic mediator and prognostic biomarker related to OC progression and poor outcomes. At the mechanistic level, TOP2A can control tumor cell growth via AKT/mTOR pathway modulation. These preliminary results provide a foundation for future research seeking to explore the utility of TOP2A inhibitor-based combination treatment regimens in platinum-resistant recurrent OC patients.