Tumor Biology最新文献

 The development of targeted therapies for non-small cell lung cancer (NSCLC), such as the epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and ROS proto-oncogene 1 (ROS1), has improved patients' prognosis and significantly extended progression-free survival. However, it remains unclear why some patients do not benefit from the treatment as much or have a rapid disease progression. It is considered that, apart from the oncogenic driver gene, molecular alterations in a number of caretaker and gatekeeper genes significantly impact the efficacy of targeted therapies. The tumor protein 53 (TP53) gene is one of the most frequently mutated genes in NSCLC. To date, numerous studies have investigated the influence of various TP53 alterations on patient prognosis and responsiveness to therapies targeting EGFR, ALK, or ROS1. This review focuses on the latest data concerning the role of TP53 alterations as prognostic and/or predictive biomarkers for EGFR, ALK, and ROS1 tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Since the presence of TP53 mutations in NSCLC has been linked to its decreased responsiveness to EGFR, ALK, and ROS1 targeted therapy in most of the referenced studies, the review also discusses the impact of TP53 mutations on treatment resistance. It seems plausible that assessing the TP53 mutation status could aid in patient stratification for optimal clinical decision-making. However, drawing meaningful conclusions about the clinical value of the TP53 co-mutations in EGFR-, ALK- or ROS1-positive NSCLC is hampered mainly by an insufficient knowledge regarding the functional consequences of the TP53 alterations. The integration of next-generation sequencing into the routine molecular diagnostics of cancer patients will facilitate the detection and identification of targetable genetic alterations along with co-occurring TP53 variants. This advancement holds the potential to accelerate understanding of the biological and clinical role of p53 in targeted therapies for NSCLC.

The optimal positioning and usage of serum tumor markers (STMs) in advanced non-small cell lung cancer (NSCLC) care is still unclear. This review aimed to provide an overview of the potential use and value of STMs in routine advanced NSCLC care for the prediction of prognosis and treatment response. Radiological imaging and clinical symptoms have shown not to capture a patient's entire disease status in daily clinical practice. Since STM measurements allow for a rapid, minimally invasive, and safe evaluation of the patient's tumor status in real time, STMs can be used as companion decision-making support tools before start and during treatment. To overcome the limited sensitivity and specificity associated with the use of STMs, tests should only be applied in specific subgroups of patients and different test characteristics should be defined per clinical context in order to answer different clinical questions. The same approach can similarly be relevant when developing clinical applications for other (circulating) biomarkers. Future research should focus on the approaches described in this review to achieve STM test implementation in advanced NSCLC care.

Background: It is well established that most colorectal carcinomas arise from conventional adenomas through the adenoma-carcinoma sequence (ACS) model. mitogen-activated protein kinases (MAPKs) pathway has been reported as a crucial player in tumorigenesis. The MAPK signaling pathway is activated by different extracellular signals involving the "mitogen-activated/extracellular signal-regulated kinase 1 (MEK1)", and this induces the expression of genes involved in proliferation and cellular transformation. Diaphanous-related formin-3 (DIAPH3) acts as a potential metastasis regulator through inhibiting the cellular transition to amoeboid behavior in different cancer types.

Objective: The aim of the study was to investigate the pattern of immunohistochemical expression of MEK1 and DIAPH3 in colorectal adenoma (CRA) and corresponding colorectal carcinoma (CRC) specimens.

Methods: The immunohistochemical expression of DIAPH3 and MEK1 was examined in 43 cases of CRC and their associated adenomas using tissue microarray technique.

Results: MEK1 was overexpressed in 23 CRC cases (53.5%) and in 20 CRA cases (46.5%). DIAPH3 was overexpressed in 11 CRA cases (about 29%) which were significantly lower than CRC (22 cases; 58%) (P = 0.011). Both MEK1 and DIAPH3 overexpression were significantly correlated in CRC (P = 0.009) and CRA cases (P = 0.002). Tumors with MEK1 overexpression had a significantly higher tumor grade (P = 0.050) and perineural invasion (P = 0.017).

Conclusions: Both MEK1 and DIAPH3 are overexpressed across colorectal ACS with strong correlation between them. This co- expression suggests a possible synergistic effect of MEK1 and DIAPH-3 in colorectal ACS. Further large-scale studies are required to investigate the potential functional aspects of MEK1 and DIAPH3 in ACS and their involvement in tumor initiation and the metastatic process.

Background: Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce the synthesis of TMs, and the release of these molecules into the bloodstream allows their quantification in biological fluids. Although very small concentrations of TMs are usually present in the serum or plasma of healthy subjects, increased concentrations may also be found in the presence of benign diseases or due to technical interference, producing false positive results.

Material and methods and results: Our review analyses the causes of false positives described between January 1970 to February 2023 for the TMs most frequently used in clinical practice: α-fetoprotein (AFP), β2-microglobulin (β2-M), cancer antigen 15-3 (CA 15-3), cancer antigen CA 19-9 (CA 19-9), cancer antigen CA 72-4 (CA 72-4), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), chromogranin A (CgA), choriogonadotropin (hCG), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), human epididymis protein 4 (HE4), serum HER2 (sHER2), squamous cell carcinoma antigen (SCCA), protein induced by vitamin K absence-II (PIVKA-II), Pro-gastrin-releasing peptide (Pro-GRP), prostate-specific antigen (PSA), Protein S-100 (S-100) and thyroglobulin (Tg). A total of 247 references were included.

Conclusions: A better understanding of pathophysiological processes and other conditions that affect the concentration of TMs might improve the interpretation of results and their clinical application.

Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple types of cancer, including patients with non-small cell lung cancer (NSCLC). Indeed, NSCLC was the first malignancy in which measurement of ctDNA was approved for clinical use, i.e., mutational testing of EGFR for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced disease. Although historically the gold standard method for EGFR mutational analysis required tumor tissue, the use of ctDNA is more convenient and safer for patients, results in a faster turn-around-time for return of results, provides a more complete representation of genetic alteration in heterogeneous tumors and is less costly to perform. Emerging uses of ctDNA in patients with lung or suspected lung cancer include screening for early disease, surveillance following initial treatment and monitoring response to therapy in metastatic disease. For evaluating therapy response, ctDNA appears to be especially useful in patients receiving targeted therapies against driver oncogenes or immunotherapy. Further work should not only validate these emerging findings but also aim to optimize and standardize ctDNA assays.

Background: Lack of druggable targets and complex expression heterogeneity of known targets is common among TNBC subtypes. An enhanced expression of galectin-3 in TNBCs has already been documented. We have observed a tumor progression-dependent galectin-3 expression in TNBCs compared to adjacent epithelium and non TNBCs.

Objective: To unravel the association of galectin- 3 in tumor progression, aggressiveness and drug resistance in TNBC patients.

Methods: Galectin-3 expression in 489 breast cancer tissues was correlated with clinicopathological features and the results were validated in cell lines and mouse model by silencing galectin-3 using shRNA and the proteins were profiled by western blot and qRT-PCR. Protein interaction was analyzed by GFP Trap and Mass spectrometry.

Results: Galectin-3 expression correlated with tumor stage in TNBC and a lower galectin-3 expression was associated with poor patient survival. The positive correlation between galectin-3, vimentin and CD44 expression, pinpoints galectin-3 contribution to epithelial to mesenchymal transition, drug resistance and stemness. Vimentin was found as an interacting partner of galectin-3. Duplexing of galecin-3 and vimentin in patient samples revealed the presence of tumor cells co-expressing both galectin-3 and vimentin. In vitro studies also showed its role in tumor cell survival and metastatic potential, elementary for tumor progression. In vivo studies further confirmed its metastatic potential.

Conclusions: Tumor progression dependent expression pattern of galectin 3 was found to indicate prognosis. Co-expression of galectin-3 and vimentin in tumor cells promotes tumor dissemination, survival and its metastatic capability in TNBCs.