Tumor Biology最新文献

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.

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.

Background: Hypoxia is the most common signature of the tumor microenvironment that drives tumorigenesis through the complex crosstalk of a family of transcription factors called hypoxia-inducible factors (HIFs), with other intercellular signaling networks. Hypoxia increases transforming growth factor-beta (TGF-β) expression. TGF-β and HIF-1α play critical roles in several malignancies and their interactions in melanoma progression remain unknown. Therefore, the aim of this study was to assess the impact of inhibiting activin receptor-like kinase-5 (ALK5), a TGF-β receptor, on the response to HIF-1α activation or inhibition in melanoma tumor progression.

Materials and methods: Tumors were induced in C57BL/6J mice by subcutaneous inoculation with B16F10 melanoma cells. Mice were divided into HIF-1α inhibitor, ALK5 inhibitor (1 mg/kg) and HIF-1α inhibitor (100 mg/kg), ALK5 inhibitor, HIF-1α activator (1000 mg/kg), HIF-1α activator and ALK5 inhibitor, and control groups to receive inhibitors and activators through intraperitoneal injection. The expression of E-cadherin was evaluated by RT-qPCR. Vessel density and platelet-derived growth factor receptor beta (PDGFR)-β+ cells around the vessels were investigated using immunohistochemistry.

Results: The groups receiving HIF-1α inhibitor and activator showed lower and higher tumor growth compared to the control group, respectively. E-cadherin expression decreased in all groups compared to the control group, illustrating the dual function of E-cadherin in the tumor microenvironment. Vascular density was reduced in the groups given HIF-1α inhibitor, ALK5 inhibitor, and ALK5 and HIF-1α inhibitor simultaneously. The percentage of PDGFR-β+ cells was reduced in the presence of HIF-1α inhibitor, ALK5 inhibitor, HIF-1α and ALK5 inhibitors, and upon simultaneous treatment with HIF-1α activator and ALK5 inhibitor.

Conclusion: Despite increased expression and interaction between TGF-β and HIF-1α pathways in some cancers, in melanoma, inhibition of either pathway alone may have a stronger effect on tumor inhibition than simultaneous inhibition of both pathways. The synergistic effects may be context-dependent and should be further evaluated in different cancer types.

Background: Cervical cancers (CaCx), like many other cancer types, portray high molecular heterogeneity that affects response to therapy, including immunotherapy. In India and other developing countries, CaCx mortality rates are very high because women report to the clinics with advanced cancers in absence of organized screening programs. This calls for implementation of newer therapeutic regimens for CaCx, like immunotherapy, which is again not used commonly in such countries.

Objective: Therefore, we focused on dissecting tumour immune heterogeneity, if any, identify immune gene-based biomarkers of heterogeneity and subsets of such cancers with the potential for immunotherapy. We also attempted to characterize the cancer-associated phenotypes of such subsets, including viral load, to decipher the relationship of tumour immunogenicity with oncogenicity.

Methods: Employing RNA-seq analysis of 44 HPV16 positive CaCx patients, immune subtypes were identified by unsupervised hierarchical clustering of global immune-gene expression profiles. Proportions of tumor infiltrating immune cells in the tumor milieu were estimated, employing Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), using gene expression data from RNA-seq. The oncogenic phenotypes of the immune subtypes of CaCx were deciphered through differential gene expression (DEGs) and pathway enrichment analysis. Viral load was estimated through TaqMan-based qRT-PCR analysis.

Results: Analysis revealed the presence of two immune subtypes of CaCx, A (26/44; 59.09%) and B (18/44; 40.90%). Compared to Subtype-A, Subtype-B portrayed overexpression of immune genes and high infiltration of immune cells, specifically CD8+ T cells (p < 0.0001). Besides, a significant correlation between PD-1 and PD-L1 co-expression among Subtype-B, as opposed to Subtype-A, confirmed the interactive roles of these immune checkpoint molecules in Subtype B. Stepwise discriminant analysis pin-pointed ten immune-genes that could classify 100% of the patients significantly (p < 0.0001) into the two immune subtypes and serve as potential biomarkers of CaCx immunity. Differential gene expression analysis between the subtypes unveiled that Subtype-B was more biologically aggressive than Subtype-A, reflecting loss of structural integrity and promotion of cancer progression. The viral load was significantly lower in Subtype-B (average viral load = 10.74/100 ng of genomic DNA) compared to Subtype-A (average viral load = 14.29/100 ng of genomic DNA). Thus viral load and the ten-gene panel underscore their association with immunogenicity and oncogenicity.

Conclusion: Our study provides strong evidence that only a subset, about 41% of HPV16 positive CaCx patients in India, portray immune enrichment of the tumor milieu coupled with aggressive phenotypes. Such subtypes are therefore likely