MATERIAL AND METHODS: qRT-PCR and flow cytometry were performed to evaluate mRNA and protein expression of XCR1 and hLtn. Recombinant hLtn variants (wild-type, CC3 and W55D mutant) were designed, expressed, purified and evaluated using proliferation, adhesion and chemotaxis assays. XCR1 and hLtn expression regulation by fibroblasts was determined using indirect co-culture. XCR1 and hLtn expression in primary and metastatic OSCC tissue was assessed using immunohistochemistry.
RESULTS: hLtn caused a significant decrease in OCCL XCR1 surface protein expression. hLtn CC3 mutant was highly functional facilitating proliferation and migration. Conditioned media from primary cancer-associated and senescent fibroblasts significantly upregulated XCR1 and hLtn mRNA expression in OCCL. Immunohistochemistry revealed higher XCR1 and hLtn expression in metastatic tumour deposits and surrounding stroma compared to primary OSCC tissue.
CONCLUSIONS: The development of hLtn biological mutants, regulation of XCR1 expression by its ligand hLtn and crosstalk with fibroblasts are novel findings suggesting an important role for the XCR1/hLtn axis within the OSCC tumour microenvironment. These discoveries build upon previous studies and suggest that the hLtn/XCR1 axis has a significant role in stromal crosstalk and OSCC progression.
Aims: To assess the OCT4 stemness factor in oral leukoplakia for its potential risk to malignant transformation.
Settings and Design: 20 cases of oral leukoplakia were obtained from archives at Oral Cancer Research & Coordinating center (OCRCC) Malaysia Subjects and Methods: 20 cases of oral leukoplakia were assessed by OCT4 immunohistochemically. Oral squamous cell carcinoma was used as a control.
Result: no expression of OCT 4 was observed in any cases of oral leukoplakia.
Conclusion: The molecular mechanisms of Oct4 regulation and in particular of its switch on and off in tissues depends upon its microenvironment, which makes it challenging in fundamental and applied research fields of regenerative medicine and cancer therapy. It's better that patients should undergo multiple biopsies for the early detection of malignant transformation with close follow-up during the first two to three years, a large amount of work remains to be done with multi-marker panel investigation, as cure rates have remained constant over three decades.
MAIN BODY: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME.
CONCLUSIONS: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.
METHODS: Transcriptomic and clinical data pertaining to LUAD were retrieved from open-access databases to establish an association between mRNA expression profiles and the presence of TDP-43. A risk-prognosis model was developed to compare patient survival rates across various groups, and its accuracy was also assessed. Additionally, differences in tumor stemness, mutational profiles, tumor microenvironment (TME) characteristics, immune checkpoints, and immune cell infiltration were analyzed in the different groups. Moreover, the study entailed predicting the potential response to immunotherapy as well as the sensitivity to commonly employed chemotherapeutic agents and targeted drugs for each distinct group.
RESULTS: The TDP-43 Co-expressed Gene Risk Score (TCGRS) model was constructed utilizing four genes: Kinesin Family Member 20A (KIF20A), WD Repeat Domain 4 (WDR4), Proline Rich 11 (PRR11), and Glia Maturation Factor Gamma (GMFG). The value of this model in predicting LUAD patient survival is effectively illustrated by both the Kaplan-Meier (K-M) survival curve and the area under the receiver operating characteristic curve (AUC-ROC). The Gene Set Enrichment Analysis (GSEA) revealed that the high TCGRS group was primarily enriched in biological pathways and functions linked to DNA replication and cell cycle; the low TCGRS group showed primary enrichment in immune-related pathways and functions. The high and low TCGRS groups showed differences in tumor stemness, mutational burden, TME, immune infiltration level, and immune checkpoints. The predictions analysis of immunotherapy indicates that the Tumor Immune Dysfunction and Exclusion (TIDE) score (p
MAIN BODY: This review highlights the roles of CSCs in tumour initiation, progression and metastasis with a focus on the cellular and molecular regulators that influence their phenotypical changes and behaviours in the different stages of cancer progression. We delineate the cross-talks between CSCs with the tumour microenvironment that support their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation in response to therapeutic pressure. An insight into the distinct roles of CSCs in promoting angiogenesis and metastasis has been captured based on in vitro and in vivo evidences.
CONCLUSION: Given dynamic cellular events along the cancer progression and contributions of resistance nature by CSCs, understanding their molecular and cellular regulatory mechanism in a heterogeneous nature, provides significant cornerstone for the development of CSC-specific therapeutics.