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World Journal of Gastrointestinal... Apr 2024Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that...
BACKGROUND
Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors. In this context, Accumulated data suggests that pathological evaluation of tumor budding (TB), desmoplastic reaction (DR), and tumor-infiltrating lymphocytes (TILs) may be crucial in determining tumor behavior in the gastrointestinal tract. Regarding gastric adenocarcinoma (GAC), although some results suggest that TB and TILs may be effective in determining the course of the disease, the data do not agree. Moreover, very few studies have investigated the relationship between DR and survival. At present, the associations between tumor TB, DR and TILs in GAC patients have not been determined.
AIM
To establish the relationships between TB, DR, and TILs in patients with GAC and to assess their influence on prognosis.
METHODS
Our study group comprised 130 patients diagnosed with GAC. The definition of TB was established based on the International TB Consensus Conference. The DR was categorized into three groups according to the level of tumor stroma maturation. The assessment of TILs was conducted using a semiquantitative approach, employing a cutoff value of 5%. The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27.
RESULTS
A significant correlation between peritumoral budding (PTB) and intratumoral budding (ITB) was noted ( = 0.943). Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs ( 0.01). PTB and ITB were associated with histological subtype, lymph node metastasis (LNM), and stage ( 0.01). ITB, PTB, LNM, DR, and stage were significant risk factors associated with poor prognosis. The multivariate Cox regression analysis identified ITB, PTB, and LNM as independent prognostic variables ( 0.05). In intestinal-type adenocarcinomas, a positive correlation between PTB and ITB was noted ( = 0.972). While univariate analysis revealed that LNM, stage, PTB, ITB, and DR were strong parameters for predicting survival ( 0.05), only PTB and ITB were found to be independent prognostic factors ( 0.001).
CONCLUSION
TB may be a potential prognostic marker in GAC. However, further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.
PubMed: 38682027
DOI: 10.4291/wjgp.v15.i1.91237 -
International Journal of Molecular... Apr 2024Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal...
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.
Topics: Humans; Male; Female; Lymphatic Metastasis; Middle Aged; Aged; Skin Neoplasms; Head and Neck Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Prognosis; Carcinoma, Squamous Cell; Aged, 80 and over; Biomarkers, Tumor; Squamous Cell Carcinoma of Head and Neck; Adult; Kaplan-Meier Estimate; Proportional Hazards Models; Immunohistochemistry
PubMed: 38673889
DOI: 10.3390/ijms25084304 -
Cancers Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.
PubMed: 38672552
DOI: 10.3390/cancers16081470 -
World Journal of Gastrointestinal... Apr 2024Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it... (Review)
Review
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as , and are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
PubMed: 38660642
DOI: 10.4251/wjgo.v16.i4.1134 -
Scientific Reports Apr 2024Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that...
Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that impacts interactions with cells in the tumor microenvironment (TME). Thus, there is a pressing need for models to probe the contributions of cellular and noncellular crosstalk. Organoids are promising model systems with the potential to generate a plethora of data including phenotypic, transcriptomic and genomic characterization but still require improvements in culture conditions mimicking the TME. Here, we describe an INTERaction with Organoid-in-MatriX ("InterOMaX") model system, that presents a 3D co-culture-based platform for investigating matrix-dependent cellular crosstalk. We describe its potential to uncover new molecular mechanisms of T cell responses to murine KPC (LSL-Kras/Trp53/p48) PDAC cells as well as PDAC patient-derived organoids (PDOs). For this, a customizable matrix and homogenously sized organoid-in-matrix positioning of cancer cells were designed based on a standardized agarose microwell chip array system and established for co-culture with T cells and inclusion of stromal cells. We describe the detection and orthogonal analysis of murine and human PDAC cell populations with distinct sensitivity to T cell killing that is corroborated in vivo. By enabling both identification and validation of gene candidates for T cell resistance, this platform sets the stage for better mechanistic understanding of cancer cell-intrinsic resistance phenotypes in PDAC.
Topics: Organoids; Animals; Pancreatic Neoplasms; Mice; Carcinoma, Pancreatic Ductal; Humans; T-Lymphocytes; Tumor Microenvironment; Coculture Techniques; Cell Line, Tumor
PubMed: 38654067
DOI: 10.1038/s41598-024-60107-5 -
The Journal of Clinical Investigation Apr 2024CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM)...
CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.
Topics: CD8-Positive T-Lymphocytes; Animals; Tumor Microenvironment; Mice; YAP-Signaling Proteins; Humans; Extracellular Matrix; Sarcoma; Collagen Type VI; Adaptor Proteins, Signal Transducing; Transcription Factors; Oncogenes; Neoplasm Proteins; Collagen Type I
PubMed: 38652549
DOI: 10.1172/JCI167826 -
Clinical and Experimental... 2024Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are... (Review)
Review
Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC's well-established immunologically "cold" tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.
PubMed: 38650920
DOI: 10.2147/CEG.S390655 -
Journal of Nanobiotechnology Apr 2024Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the... (Review)
Review
Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.
Topics: Cancer-Associated Fibroblasts; Exosomes; Tumor Microenvironment; Humans; Animals; Neoplasms; Drug Delivery Systems; Extracellular Matrix; Antineoplastic Agents
PubMed: 38644492
DOI: 10.1186/s12951-024-02452-1