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BMC Cancer Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are areas at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression.
METHODS
We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised.
RESULTS
In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68 macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm and 1812 ± 1008 µm for the SARIFA-negative and -positive cases, respectively (p < 0.001).
CONCLUSIONS
SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
Topics: Humans; Carcinoma, Pancreatic Ductal; Female; Male; Biomarkers, Tumor; Prognosis; Pancreatic Neoplasms; Aged; Middle Aged; Fatty Acid-Binding Proteins; Neoplasm Invasiveness; Tumor Microenvironment; Lipid Metabolism; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Stromal Cells; CD36 Antigens; Adipocytes; Adult; Aged, 80 and over; CD68 Molecule
PubMed: 38926671
DOI: 10.1186/s12885-024-12519-9 -
Surgical Laparoscopy, Endoscopy &... Jun 2024The adequacy of lymph node (LN) harvest is important in oncological colon cancer resections. While several studies have suggested factors influencing LN yield in colon...
PURPOSE
The adequacy of lymph node (LN) harvest is important in oncological colon cancer resections. While several studies have suggested factors influencing LN yield in colon cancer, limited data are available only regarding right hemicolectomies with complete mesocolic excision (CME) and central vessel ligation (CVL).
METHODS
A retrospective analysis was conducted on 169 patients who underwent right hemicolectomies with CME and CVL for right-sided colon cancer between February 2019 and March 2023. The patients were divided into 2 groups: groups with ≤24 LN yield and >24 LN yield, and the patient, surgical, and pathologic factors, which could potentially influence the LN yield, were analyzed.
RESULTS
Younger age, lower American Society of Anesthesiologists (ASA) classification, and advanced clinical TNM (cTNM) stage among patient factors, the presence of obstructions regarding the surgical factors, and the presence of desmoplastic tumor reaction in the pathologic factors were more likely to harvest >24 LNs. In a multivariate analysis, younger age, lower ASA classification, advanced cTNM stage, and an ileocolic artery (ICA) crossing pattern posterior to the superior mesenteric vein (SMV) were independently associated with a >24 LN harvest. Patients with cTNM 3,4 showed the tendency of > 24 LN yield consistently within each subgroup, irrespective of the age, ASA classification, and ileocolic artery crossing pattern.
CONCLUSIONS
Our investigation revealed a significant correlation between the advanced preoperative clinical stage and an increased number of harvested lymph nodes (LNs) in patients undergoing right hemicolectomies with CME a CVL. The observed association is potentially influenced by tumor aggressiveness and the extent of surgical resection performed by the surgeon. To elucidate the intricate relationship between surgical outcomes and the quantity of LN harvest in patients subjected to standardized CME and CVL for right-sided colon cancer, further dedicated research is warranted.
PubMed: 38919070
DOI: 10.1097/SLE.0000000000001301 -
BioRxiv : the Preprint Server For... Jun 2024Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection...
Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI compared with VI tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42×10 ) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI LUAD (HR=2.76; p=0.003). To determine our VI predictor's robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2×10 ) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.
PubMed: 38915565
DOI: 10.1101/2024.06.07.597993 -
Pancreas Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and lack of effective diagnostic and prognostic biomarkers. A rich and activated desmoplastic...
OBJECTIVES
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and lack of effective diagnostic and prognostic biomarkers. A rich and activated desmoplastic tumor stroma is considered a hallmark of PDAC, and therefore stromal components could be a source of possible new prognostic biomarkers. Expression of collagen VI (COL6) has been found to associate with prognosis in many forms of cancer but has been less extensively studied in PDAC. Some previous studies indicate that COL6 expression is upregulated in PDAC, and it could have prognostic value.
METHODS
In this study the expression of COL6 was analyzed by immunohistochemistry in tissue microarrays (TMAs) containing tumor tissue samples from 164 (n = 164) PDAC patients who had undergone surgical resection. Scoring results were combined with clinical data, and the prognostic significance of COL6 was estimated with Kaplan-Meier survival estimates and multivariable Cox regression analysis. COL6 protein expression patterns were further investigated in The Cancer Proteome Atlas (TCPA) dataset (n = 103) and in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset (n = 138). COL6 mRNA expression in PDAC tissue was investigated using The Cancer Genome Atlas (TCGA) by forming a dataset containing gene expression data and corresponding clinical variables of 168 (n = 168) PDAC patients.
RESULTS
In this large PDAC TMA cohort we could not find statistically significant (p < 0.05) differences in survival when comparing patients with high and low protein expression of any of the analyzed COL6 α-chains (α1(VI): HR 0.90, 95% CI 0.64-1.28; α2(VI): HR 1.28, 95% CI 0.86-1.89; α3(VI): HR 0.91, 95%CI 0.64-1.29). Similar results were obtained when assessing expression of COL6 in public data from TCPA, CPTAC and TCGA.
CONCLUSIONS
In contrast with previous studies and some other cancer forms, we did not find any association of COL6 tissue expression and PDAC survival on protein or mRNA level.
PubMed: 38913551
DOI: 10.1097/MPA.0000000000002360 -
Journal of Orthopaedic Case Reports Jun 2024Desmoplastic fibroblastoma is a rare, slow-growing benign soft tissue tumor. It has a wide anatomical distribution and mainly affects adult males. Fourteen percent of...
INTRODUCTION
Desmoplastic fibroblastoma is a rare, slow-growing benign soft tissue tumor. It has a wide anatomical distribution and mainly affects adult males. Fourteen percent of cases occur in the ankle or foot.
CASE REPORT
In this study, we report a rare location of desmoplastic fibroblastoma on the ankle of a 76-year-old female, discovered as a slowly growing mass.
DISCUSSION
Desmoplastic fibroblastoma is an anatomical and clinical entity. It appears macroscopically as a pseudocartilaginous structure and histologically as a stellate or spindle-shaped fibroblastic proliferation in a collagenous stroma.
CONCLUSION
Desmoplastic fibroblastoma has anatomical specificities and should still be clearly distinguished from certain malignant tumors.
PubMed: 38910994
DOI: 10.13107/jocr.2024.v14.i06.4516 -
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 2024Prognostic stratification is an urgent concern for patients with colorectal cancer (CRC). The desmoplastic reaction (DR) is speculated to mirror the tumor...
Prognostic stratification is an urgent concern for patients with colorectal cancer (CRC). The desmoplastic reaction (DR) is speculated to mirror the tumor microenvironment. DR types are considered independent prognostic indicators in CRC, but have not been incorporated in previous prognostic nomograms. We aimed to assess the prognostic significance of a novel approach incorporating histopathological indicators reflecting tumor glandular differentiation and microenvironment. We evaluated 329 consecutive patients with CRC who underwent surgical resection at Kansai Medical University. Histological glandular differentiation was scored as 2 (0 point), 3 (1 point), or 4 (2 points). Tumor buddings (TBs) were classified as TB1 (0 point), TB2 (1 point), or TB3 (2 points). pT1 or 2 was considered as 0 point, pT3 or 4 + DR non-immature type as 1 point, and pT3 or 4 + DR immature type as 2 points. Lymph node metastasis was classified as pN0 (0 point), pN1 (1 point), or pN2 (2 points). The preoperative carcinoembryonic antigen levels were categorized as < 5.0 ng/mL (0 point) and ≧5.0 (1 point). Considering these factors, the following D&M (tumor differentiation and microenvironment) scoring system was applied: I (0-2 points), II (3-4 points), III (5-6 points), and IV (7-9 points). Kaplan-Meier curves showed significant differences in disease-specific survival and recurrence-free survival among the assigned scores, highlighting their enhanced utility compared with the American Joint Committee on Cancer 8th edition staging system. The D&M scoring system was valuable as the initial prognostic nomogram, including DR.
Topics: Humans; Colorectal Neoplasms; Female; Male; Tumor Microenvironment; Aged; Prognosis; Middle Aged; Aged, 80 and over; Adult; Cell Differentiation; Neoplasm Staging; Lymphatic Metastasis; Nomograms
PubMed: 38902294
DOI: 10.1038/s41598-024-65015-2 -
F1000Research 2022Various stemness markers (SOX2, OCT4, and NANOG) have been studied in odontogenic cysts and tumors. However, studies on SALL4 having similar properties of stemness has...
BACKGROUND
Various stemness markers (SOX2, OCT4, and NANOG) have been studied in odontogenic cysts and tumors. However, studies on SALL4 having similar properties of stemness has not been documented. Additionally, insight into fascin as a migratory molecule is less explored. In this study, the expression of SALL4 and fascin were evaluated in ameloblastoma, adenomatoid odontogenic tumor (AOT), odontogenic keratocyst (OKC), dentigerous cyst (DC), radicular cyst (RC), and calcifying odontogenic cyst (COC).
METHODS
Semi-quantitative analysis of fascin and SALL4 immuno-positive cells was done in a total of 40 cases of ameloblastoma (11 plexiform, 12 follicular, 12 unicystic, and 5 desmoplastic) variants, 6 cases of AOT, 15 each of OKC, DC, RC and 5 of COC. Chi-square test was applied to evaluate the association between SALL4 and fascin expression in odontogenic cysts and tumors.
RESULTS
Fascin immunopositivity was observed in peripheral ameloblast-like cells, and weak or absent in stellate reticulum-like cells. A moderate to weak immune-reactivity to SALL4 was observed in the cytoplasm of ameloblastoma, epithelial cells of dentigerous and radicular cysts, having a marked inflammatory infiltrate, which is an interesting observation. COC and AOT had negative to weak expressions. No recurrence has been reported.
CONCLUSIONS
Expression of fascin in ameloblastomas elucidate their role in motility and localized invasion. Its expression in less aggressive lesions like DC, COC, AOT will incite to explore the other functional properties of fascin. SALL4 expression in the cytoplasm of odontogenic cysts and tumors may represent inactive or mutant forms which requires further validation.
Topics: Humans; Transcription Factors; Microfilament Proteins; Odontogenic Cysts; Carrier Proteins; Immunohistochemistry; Ameloblastoma; Odontogenic Tumors; Biomarkers, Tumor
PubMed: 38895097
DOI: 10.12688/f1000research.126091.3 -
International Journal of Molecular... May 2024Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane...
Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds β1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and β1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12-mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFβ signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.
Topics: Humans; Animals; ADAM12 Protein; Mice; Extracellular Matrix Proteins; Basigin; Protein Binding; Mice, Nude; Protein Domains; Cell Movement; MCF-7 Cells; Gene Expression Regulation, Neoplastic; Neoplasms; Female; Cell Line, Tumor; Extracellular Matrix
PubMed: 38892056
DOI: 10.3390/ijms25115871 -
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