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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 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 -
International Journal of Molecular... May 2024Pancreatic ductal adenocarcinoma (PDAC), characterized by hypovascularity, hypoxia, and desmoplastic stroma is one of the deadliest malignancies in humans, with a 5-year...
Pancreatic ductal adenocarcinoma (PDAC), characterized by hypovascularity, hypoxia, and desmoplastic stroma is one of the deadliest malignancies in humans, with a 5-year survival rate of only 7%. The anatomical location of the pancreas and lack of symptoms in patients with early onset of disease accounts for late diagnosis. Consequently, 85% of patients present with non-resectable, locally advanced, or advanced metastatic disease at diagnosis and rely on alternative therapies such as chemotherapy, immunotherapy, and others. The response to these therapies highly depends on the stage of disease at the start of therapy. It is, therefore, vital to consider the stages of PDAC models in preclinical studies when testing new therapeutics and treatment modalities. We report a standardized induction of cell-based orthotopic pancreatic cancer models in mice and the identification of vital features of their progression by ultrasound imaging and histological analysis of the level of pancreatic stellate cells, mature fibroblasts, and collagen. The results highlight that early-stage primary tumors are secluded in the pancreas and advance towards infiltrating the omentum at week 5-7 post implantation of the BxPC-3 and Panc-1 models investigated. Late stages show extensive growth, the infiltration of the omentum and/or stomach wall, metastases, augmented fibroblasts, and collagen levels. The findings can serve as suggestions for defining of orthotopic pancreatic cancer models for the preclinical testing of drug efficacy in the future.
Topics: Animals; Pancreatic Neoplasms; Mice; Carcinoma, Pancreatic Ductal; Humans; Disease Models, Animal; Cell Line, Tumor
PubMed: 38891809
DOI: 10.3390/ijms25115619 -
Cureus May 2024Primary orbital melanoma and metastatic cutaneous melanoma of the orbit are extremely rare. Desmoplastic melanoma (DM) is an infrequent variant of melanoma that can...
Primary orbital melanoma and metastatic cutaneous melanoma of the orbit are extremely rare. Desmoplastic melanoma (DM) is an infrequent variant of melanoma that can extend from a superficial location into deep tissues by neurotropic mechanisms. A 78-year-old male was referred to us with a periocular mixed malignant melanoma (spindle cell melanoma with desmoplastic reaction) in his left lower eyelid with uncontrollable disease (orbital and inferior orbital rim invasion) despite treatment. The surgical technique consisted of an extended orbital exenteration, maxillectomy, and ethmoidectomy, with a 2 cm macroscopic surgical margin. We performed a delayed socket reconstruction with a temporalis muscle flap using a transorbital approach. The patient remained disease-free for 1.5 years with a good quality of life since exenteration surgery. At this time, he presented a recurrence in the area of the malar scar with a new orbital invasion, and finally, he died due to mediastinal, pleural, and pulmonary metastasis. The treatment of a cutaneous melanoma arising in the periocular region is a challenging reconstructive problem and it may compromise the globe and visual function.
PubMed: 38887344
DOI: 10.7759/cureus.60541 -
Radiology Case Reports Aug 2024We report a case of a 44-year-old male patient, who presented to the University Hospital of Salzburg, Austria with abdominal pain, persistent jaundice, and lack of...
We report a case of a 44-year-old male patient, who presented to the University Hospital of Salzburg, Austria with abdominal pain, persistent jaundice, and lack of appetite. Radiological work-up (CT, MRI, PET/CT) indicated a suspicious mass of the uncinate process of the pancreatic head with adjacent infiltration and regional lymphadenopathy. The differential diagnosis was between primary pancreatic cancer and focal autoimmune pancreatitis. Further laparoscopic biopsies from multiple areas, showed only fibrous scarring processes, with no malignancy. Treatment with steroids didn't give any benefits. After multiple follow-up CTs and MRs within 6 months-additional biopsies were done, which eventually demonstrated adenocarcinoma. Evidently the cancer diagnosis was much delayed and the patient started receiving chemotherapy, but radical surgery was not possible. Multiple articles and case reports can be found in the literature, that are reviewing the fact that pancreatic inflammatory processes are mimicking pancreatic tumor, but not many articles or case reports are available in the literature, where neoplastic processes are misinterpreted as inflammatory and incorrectly proven with histological examination. One of the main reasons for improper diagnosis is the desmoplastic reaction around the pancreatic malignancy. Another important aspect is the acceptance of histological diagnosis as conclusive, where no opposing arguments are specified, based on radiological criteria.
PubMed: 38881618
DOI: 10.1016/j.radcr.2024.05.025 -
Turkish Neurosurgery Jan 2024Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and...
AIM
Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and 2021 WHO classifications, as WNT-activated, SHH-activated and TP53-wild type, SHH-activated and TP53-mutant, and non-WNT/non-SHH. However, the molecular methods to determine these subgroups are not easily accessible for routine testing as they are expensive. Here, we investigated the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of MB.
MATERIAL AND METHODS
β-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series.
RESULTS
Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype; 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study.
CONCLUSION
The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.
PubMed: 38874255
DOI: 10.5137/1019-5149.JTN.45863-23.2 -
BioRxiv : the Preprint Server For... May 2024Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC's poor prognosis and resistance to immunotherapy are attributed in part to its...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC's poor prognosis and resistance to immunotherapy are attributed in part to its dense, fibrotic tumor microenvironment (TME), which is known to inhibit immune cell infiltration. We recently demonstrated that PDAC patients with higher natural killer (NK) cell content and activation have better survival rates. However, NK cell interactions in the PDAC TME have yet to be deeply studied. We show here that NK cells are present and active in the human PDAC TME.
METHODS
We used imaging mass cytometry (IMC) to assess NK cell content, function, and spatial localization in human PDAC samples. Then, we used CellChat, a tool to infer ligand-receptor interactions, on a human PDAC scRNAseq dataset to further define NK cell interactions in PDAC.
RESULTS
Spatial analyses showed for the first time that active NK cells are present in the PDAC TME, and both associate and interact with malignant epithelial cell ducts. We also found that fibroblast-rich, desmoplastic regions limit NK cell infiltration in the PDAC TME. CellChat analysis identified that the CD44 receptor on NK cells interacts with PDAC extracellular matrix (ECM) components such as collagen, fibronectin and laminin expressed by fibroblasts and malignant epithelial cells. This led us to hypothesize that these interactions play roles in regulating NK cell motility in desmoplastic PDAC TMEs. Using 2D and 3D assays, we found that CD44 neutralization significantly increased NK cell invasion through matrix.
CONCLUSIONS
Targeting ECM-immune cell interactions may increase NK cell invasion into the PDAC TME.
PubMed: 38853982
DOI: 10.1101/2024.05.23.593868