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Pathology Oncology Research : POR 2024The desmoplastic reaction is considered a promising prognostic parameter for colorectal cancer. However, intermediate desmoplastic reaction is characterized by sizeable...
BACKGROUND
The desmoplastic reaction is considered a promising prognostic parameter for colorectal cancer. However, intermediate desmoplastic reaction is characterized by sizeable stromal heterogeneity, including both small amounts of keloid-like collagen (KC) in the fibrotic stroma and thick tufts of KC circumferentially surrounding cancer nests and occupying most of the fields of view. The present study aimed to evaluate the diagnostic and prognostic significance of KC histophenotyping with a quantitative visual assessment of its presence in the stroma of the invasive margin of TNM (The "tumor-node-metastasis" classification) stage II/III colorectal cancer (CRC).
METHODS AND RESULTS
175 resected tumors from patients with TNM stage II/III CRC were examined. Keloid-like collagen was assessed according to Ueno H. criteria. KC was assessed at the primary tumor invasive margin using Hematoxylin & Eosin and Masson's trichrome staining. The cut-off point for KC was examined using "the best cutoff approach by log-rank test." Using a cutoff point of 30%, we histologically divided fibrous stroma in the invasive area into two groups: "type A"-KC ≤ 0.3 and "type B"-KC>0.3. Type A stroma was observed in 48% of patients, type B-in 52%. The association between collagen amount and 5-year recurrence-free survival (5-RFS) was assessed using Cox regression analysis. Kaplan-Meier analysis and log-rank tests were used to assess the significance of survival analysis. Analysis of categorical variables showed that increased KC in CRC stroma predicted adverse outcomes for 5-RFS (hazard ratio [HR] = 3.143, 95%, confidence interval [CI] = 1.643-6.012, = 0.001). Moreover, in Kaplan-Meier analysis, the log-rank test showed that type B exhibited worse 5-RFS than type A ( = 0.000).
CONCLUSION
KC is an independent predictor of 5-year overall and RFS in patients with TNM stage II/III CRC treated with surgery, with worse survival rates when the amount of KC increases by >30%.
Topics: Humans; Colorectal Neoplasms; Male; Female; Prognosis; Middle Aged; Collagen; Aged; Extracellular Matrix; Keloid; Adult; Aged, 80 and over; Survival Rate; Follow-Up Studies
PubMed: 38903488
DOI: 10.3389/pore.2024.1611789 -
Scientific Reports Jun 2024Carcinogenesis and tumor proliferation are characterized by a complex interaction of cancer cells with the tumor microenvironment. In particular, a tumor-promoting...
Carcinogenesis and tumor proliferation are characterized by a complex interaction of cancer cells with the tumor microenvironment. In particular, a tumor-promoting effect can be assumed for the stroma and its fibroblasts. An influence of the immune system on non small cell lung cancer (NSCLC) is now also suspected. In our study, we examined 309 sections of squamous cell carcinoma (SCC), a subtype of NSCLC. We determined the cell densities and areas of the different tissues in SCC using the software QuPath. Spearman rank correlation showed a significant positive correlation between the different tumor cell densities and stromal cell densities, and between tumor cell densities and immune cell densities. Overall survival curves by the Kaplan-Meier method revealed a prominent negative curve in cases of low immune cell density. Based on our results, we can assume a positive influence of the tumor microenvironment, especially the stromal cells, on tumor proliferation in SCC. We have also revealed that low density of immune cells is prognostically unfavorable.
Topics: Humans; Lung Neoplasms; Carcinoma, Squamous Cell; Tumor Microenvironment; Male; Female; Aged; Prognosis; Middle Aged; Stromal Cells; Kaplan-Meier Estimate; Carcinoma, Non-Small-Cell Lung; Cell Count
PubMed: 38902361
DOI: 10.1038/s41598-024-64956-y -
Blood Jun 2024
Azab AK, Azab F, Blotta S, et al. RhoA and Rac1 GTPases play major and differential roles in stromal cell-derived factor-1-induced cell adhesion and chemotaxis in multiple myeloma. Blood. 2009;114(3):619-629.
Topics: Humans; rhoA GTP-Binding Protein; Multiple Myeloma; rac1 GTP-Binding Protein; Chemokine CXCL12; Cell Adhesion; Chemotaxis
PubMed: 38900475
DOI: 10.1182/blood.2024025276 -
FASEB Journal : Official Publication of... Jul 2024Tumor-associated macrophages (TAMs) are integral components of the tumor microenvironment. They are involved in various aspects of tumor cell biology, driving...
Tumor-associated macrophages (TAMs) are integral components of the tumor microenvironment. They are involved in various aspects of tumor cell biology, driving pathological processes such as tumor cell proliferation, metastasis, immunosuppression, and resistance to therapy. TAMs exert their tumorigenic effects by secreting growth factors, cytokines/chemokines, metabolites, and other soluble bioactive molecules. These mediators directly promote tumor cell proliferation and modulate interactions with immune and stromal cells, facilitating further tumor growth. As research into therapies targeting TAMs intensifies, there is a growing need for reliable methods to comprehend the impact of TAMs on cancer progression and to validate novel therapeutics directed at TAMs. The traditional "M1-M2" macrophage classification based on transcriptional profiles of TAMs is not only too simplistic to describe their physiological roles, it also does not explain differences observed between mouse and human macrophages. In this context, methods that assess how TAMs influence tumor or immune cells, either through direct contact or the release of soluble factors, offer a more promising approach. We describe here comprehensive protocols for in vitro functional assays to study TAMs, specifically regarding their impact on the growth of lung cancer cells. We have applied these methods to both mouse and human macrophages, achieving similar outcomes in promoting the proliferation of cancer cells. This methodology can serve as a standardized approach for testing novel therapeutic approaches, targeting TAMs with novel immunotherapeutic compounds, or utilizing gene-editing techniques. Taken together, the described methodology may contribute to our understanding of complex macrophage-tumor interactions and support the development of innovative therapeutic strategies.
Topics: Humans; Animals; Mice; Tumor Microenvironment; Tumor-Associated Macrophages; Cell Proliferation; Macrophages; Lung Neoplasms; Cell Line, Tumor; Neoplasms
PubMed: 38900063
DOI: 10.1096/fj.202400240R -
Cureus May 2024Hemangioblastoma (HBM) is a tumor distinguished by the presence of stromal cells and small vessels. These stromal cells represent stem cells, which, due to the...
Hemangioblastoma (HBM) is a tumor distinguished by the presence of stromal cells and small vessels. These stromal cells represent stem cells, which, due to the influence of the neoplasm, proliferate and differentiate into "vasoformative elements" that create new blood vessels. Hemangioblastomas resemble arteriovenous malformation (AVM) in imaging features, characterized by an apparent vascular blush, the presence of multiple feeding vessels, and evident draining veins observed on digital subtraction angiography (DSA). Our study presents a case of HBM in the right cerebellar hemisphere mimicking AVM. The patient had been diagnosed with AVM in the same location two years ago and managed with endovascular embolization. One month prior, the patient experienced severe headaches, imbalance, nausea, left ear fullness, blurry vision, and high blood pressure. The imaging feature suggests HBM rather than AVM. The patient next underwent sub-occipital craniotomy and tumor resection with external ventricular drainage (EVD) insertion. The histopathological report of the excised mass confirmed HBM. In conclusion, AVM and HBM rarely occur together. Recent research indicates that HBM and AVM have exact embryologic origins and need later genetic alterations to develop into symptomatic lesions. Further research is required to clarify the uncommon combination of these lesions.
PubMed: 38899263
DOI: 10.7759/cureus.60671 -
BMC Medical Genomics Jun 2024Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis...
BACKGROUND
Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM.
METHODS AND RESULTS
The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 naïve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets.
CONCLUSIONS
The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance.
Topics: Humans; Multiple Myeloma; Computational Biology; Prognosis; Ubiquitination; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Nomograms; Cluster Analysis
PubMed: 38898455
DOI: 10.1186/s12920-024-01937-0 -
Cancers May 2024Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic...
Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors ( = 44) and patients diagnosed with myeloproliferative neoplasia ( = 11), myelodysplastic syndromes ( = 16), or acute myeloid leukemia ( = 25) and B-Non-Hodgkin lymphoma ( = 9) with BM infiltration and acute lymphoblastic leukemia ( = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets.
PubMed: 38893194
DOI: 10.3390/cancers16112071 -
Cancers May 2024A systematic review of the diagnostic accuracy of MRI in the staging of cervical cancer was conducted based on the literature from the last 5 years. A literature search... (Review)
Review
A systematic review of the diagnostic accuracy of MRI in the staging of cervical cancer was conducted based on the literature from the last 5 years. A literature search was performed in the Cochrane Library, EMBASE, MEDLINE and PubMed databases using the MeSH terms "cervical cancer", "MRI" and "neoplasm staging". A total of 110 studies were identified, of which 8 fit the inclusion criteria. MRI showed adequate accuracy (74-95%) and high sensitivity (92-100%) in assessing stromal invasion. The data for MRI in terms of assessing vaginal and pelvic side wall involvement were wide ranging and inconclusive. In assessing lymph node metastasis, MRI showed an adequate accuracy (73-90%), specificity (75-91%) and NPV (71-96%) but poor sensitivity (52-75%) and PPV (52-75%). MRI showed high accuracy (95%), sensitivity (78-96%), specificity (87-94%), and NPV (98-100%) but poor PPV (27-42%) in detecting bladder involvement. There was a paucity of data on the use of MRI in assessing rectal involvement in cervical cancer. Overall, the literature was heterogenous in the definitions and language used, which reduced the comparability between articles. More research is required into the diagnostic accuracy of MRI in the staging of cervical cancer and there must be increased consistency in the definitions and language used in the literature.
PubMed: 38893105
DOI: 10.3390/cancers16111983 -
International Journal of Molecular... May 2024One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression....
One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.
Topics: Humans; Female; Autophagy; Cancer-Associated Fibroblasts; Ovarian Neoplasms; Glucose; Cell Line, Tumor; Tumor Microenvironment; Resveratrol; Culture Media, Conditioned; Deoxyglucose; Glycolysis
PubMed: 38891879
DOI: 10.3390/ijms25115691 -
The Journal of Pathology. Clinical... Jul 2024Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells...
Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNPDPN); a PDPN-dominant group (DCNPDPN); and a DCN-dominant group (DCNPDPN), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.
Topics: Humans; Colorectal Neoplasms; Male; Female; Biomarkers, Tumor; Cancer-Associated Fibroblasts; Aged; Middle Aged; Cluster Analysis; Immunohistochemistry; Tumor Microenvironment; Prognosis; Membrane Glycoproteins; Stromal Cells; Decorin; Adult; Aged, 80 and over; Kaplan-Meier Estimate
PubMed: 38890810
DOI: 10.1002/2056-4538.12386