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1.
J Pathol ; 256(3): 269-281, 2022 03.
Article in English | MEDLINE | ID: mdl-34738636

ABSTRACT

The spread of early-stage (T1 and T2) adenocarcinomas to locoregional lymph nodes is a key event in disease progression of colorectal cancer (CRC). The cellular mechanisms behind this event are not completely understood and existing predictive biomarkers are imperfect. Here, we used an end-to-end deep learning algorithm to identify risk factors for lymph node metastasis (LNM) status in digitized histopathology slides of the primary CRC and its surrounding tissue. In two large population-based cohorts, we show that this system can predict the presence of more than one LNM in pT2 CRC patients with an area under the receiver operating curve (AUROC) of 0.733 (0.67-0.758) and patients with any LNM with an AUROC of 0.711 (0.597-0.797). Similarly, in pT1 CRC patients, the presence of more than one LNM or any LNM was predictable with an AUROC of 0.733 (0.644-0.778) and 0.567 (0.542-0.597), respectively. Based on these findings, we used the deep learning system to guide human pathology experts towards highly predictive regions for LNM in the whole slide images. This hybrid human observer and deep learning approach identified inflamed adipose tissue as the highest predictive feature for LNM presence. Our study is a first proof of concept that artificial intelligence (AI) systems may be able to discover potentially new biological mechanisms in cancer progression. Our deep learning algorithm is publicly available and can be used for biomarker discovery in any disease setting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Adipose Tissue/pathology , Colorectal Neoplasms/pathology , Deep Learning , Diagnosis, Computer-Assisted , Early Detection of Cancer , Image Interpretation, Computer-Assisted , Lymph Nodes/pathology , Microscopy , Biopsy , Humans , Lymphatic Metastasis , Neoplasm Staging , Predictive Value of Tests , Proof of Concept Study , Reproducibility of Results , Retrospective Studies , Risk Assessment , Risk Factors
2.
J Clin Pathol ; 75(8): 545-550, 2022 Aug.
Article in English | MEDLINE | ID: mdl-34645701

ABSTRACT

BACKGROUND: Since implementing the NHS bowel cancer screening programme, the rate of early colorectal cancer (eCRC; pT1) has increased threefold to 17%, but how these lesions should be managed is currently unclear. AIM: To improve risk stratification of eCRC by developing reproducible quantitative markers to build a multivariate model to predict lymph node metastasis (LNM). METHODS: Our retrospective cohort of 207 symptomatic pT1 eCRC was assessed for quantitative markers. Associations between categorical data and LNM were performed using χ2 test and Fisher's exact test. Multivariable modelling was performed using logistic regression. Youden's rule gave the cut-point for LNM. RESULTS: All significant parameters in the univariate analysis were included in a multivariate model; tumour stroma (95% CI 2.3 to 41.0; p=0.002), area of submucosal invasion (95% CI 2.1 to 284.6; p=0.011), poor tumour differentiation (95% CI 2.0 to 358.3; p=0.003) and lymphatic invasion (95% CI 1.3 to 192.6; p=0.028) were predictive of LNM. Youden's rule gave a cut-off of p>5%, capturing 18/19 LNM (94.7%) cases and leading to a resection recommendation for 34% of cases. The model that only included quantitative factors were also significant, capturing 17/19 LNM cases (90%) and leading to resection rate of 35% of cases (72/206). CONCLUSIONS: In this study, we were able to reduce the potential resection rate of pT1 with the multivariate qualitative and/or quantitative model to 34% or 35% while detecting 95% or 90% of all LNM cases, respectively. While these findings need to be validated, this model could lead to a reduction of the major resection rate in eCRC.


Subject(s)
Colorectal Neoplasms , Stomach Neoplasms , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Humans , Lymph Nodes/pathology , Lymph Nodes/surgery , Lymphatic Metastasis/pathology , Neoplasm Invasiveness/pathology , Neoplasm Staging , Retrospective Studies , Risk Factors , Stomach Neoplasms/pathology
3.
Biochim Biophys Acta ; 1860(4): 814-24, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26825774

ABSTRACT

BACKGROUND: High levels of hyaluronan (HA) synthesis in various cancer tissues, including sarcomas, are correlated with tumorigenesis and malignant transformation. RHAMM (receptor for hyaluronic acid-mediated motility) is overexpressed during tumor development in different malignancies. ß-Catenin is a crucial downstream mediator of the Wnt signaling cascade which facilitates carcinogenic events characterized by deregulated cell proliferation. METHODS: Real-time PCR, in vitro cell proliferation assay, siRNA transfection, flow cytometry, immunoprecipitation, western blotting and immunofluorescence were utilized. RESULTS: The reduction of RHAMM expression was strongly correlated with an inhibition of HT1080 fibrosarcoma cell growth (p≤0.01). LMWHA, in a RHAMM-dependent manner increases cell growth of HT1080 cells (p≤0.01). Both basal and LMWHA dependent growth of HT1080 cells was attenuated by ß-catenin deficiency (p≤0.01). ß-Catenin cytoplasmatic deposition is positively regulated by RHAMM (p≤0.01). Immunoflourescence and immunoprecipitation suggest that RHAMM/ß-catenin form an intracellular complex. Transfection experiments identified c-myc as candidate downstream mediator of RHAMM/ß-catenin effects on HT1080 fibrosarcoma cell proliferation. CONCLUSIONS: LMWHA/RHAMM downstream signaling regulates fibrosarcoma cell growth in a ß-catenin/c-myc dependent manner. GENERAL SIGNIFICANCE: The present study suggests that RHAMM is a novel ß-catenin intracellular binding partner, protecting ß-catenin from degradation and supporting the nuclear translocation of this key cellular mediator, which results in c-myc activation and enhanced fibrosarcoma cell growth.


Subject(s)
Cell Nucleus/metabolism , Cell Proliferation , Extracellular Matrix Proteins/biosynthesis , Fibrosarcoma/metabolism , Hyaluronan Receptors/biosynthesis , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction , beta Catenin/metabolism , Active Transport, Cell Nucleus , Cell Line, Tumor , Cell Nucleus/genetics , Extracellular Matrix Proteins/genetics , Fibrosarcoma/genetics , Humans , Hyaluronan Receptors/genetics , Proto-Oncogene Proteins c-myc/genetics , beta Catenin/genetics
4.
Curr Drug Deliv ; 13(4): 500-11, 2016.
Article in English | MEDLINE | ID: mdl-26549038

ABSTRACT

BACKGROUND: Hyaluronan (HA), a glycosaminoglycan, is a key extracellular matrix (ECM) component, and has been established to contribute to fibrotic, angiogenic, inflammatory as well as processes supporting cancer development. The changes in HA deposition in different tumors have been widely studied. Indeed, a multitude of reports demonstrate that HA expression is increased in different neoplasmatic tissues including lung, colon, prostate and breast cancer. The aims of this paper are to critically and in depth discuss aspects of HA metabolism in cancer and recent developments of its utilization in cancer therapy. METHODS: Up to date research and online content are reviewed. RESULTS: The cellular roles of HA are perpetrated through molecular interactions with HA-binding proteins, called hyaladherins, including CD44 receptor as well as receptor for hyaluronan-mediated motility (RHAMM). HA binding can be followed by receptor-mediated endocytosis. Importantly, hyaladherins show an altered expression in tumor tissues. Indeed, post-translational alterations in CD44 structure have been suggested to regulate the equilibrium between the "inactive" low affinity state and the "active" high affinity state of the HA binding capacity. In this concept HA fragments can be utilized as specific targeting ligands for efficient and safe drug delivery in cancer. CONCLUSION: HA-drug bioconjugates and nanoparticles have emerged as a promising platform for drug delivery during cancer treatment as demonstrated in various pre-clinical studies. Recent developments from clinical trials indicate that the utilization of specific HA-drug bioconjugates might be approved for the medical practice in the nearest future.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Carriers , Hyaluronic Acid/administration & dosage , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Extracellular Matrix Proteins/drug effects , Humans , Hyaluronan Receptors/drug effects
5.
Adv Cancer Res ; 123: 319-49, 2014.
Article in English | MEDLINE | ID: mdl-25081535

ABSTRACT

Fibrosarcoma belongs to the sarcoma cancer group, which are spindle cell malignancies of mesenchymal origin, and owe their name to the predominant cell line that is present within the tumor. The extracellular matrix (ECM) is a complicated structure that surrounds and supports cells within tissues. Its main components are proteoglycans, collagens, glycoproteins, hyaluronan (HA), and several matrix-degrading enzymes. During cancer progression, significant changes can be observed in the structural and mechanical properties of ECM components. The ECM provides a physical scaffold to which tumor cells attach and migrate. Thus, it is required for key cellular events such as cell motility, adhesion, proliferation, invasion, and metastasis. Importantly, fibrosarcomas were shown to have a high content and turnover of ECM components including HA, proteoglycans, collagens, fibronectin, and laminin. In this review, we will focus on the HA component of fibrosarcoma ECM and critically discuss its role and involved mechanisms during fibrosarcoma pathogenesis.


Subject(s)
Extracellular Matrix Proteins/metabolism , Fibrosarcoma/metabolism , Gene Expression Regulation, Neoplastic , Hyaluronan Receptors/metabolism , Hyaluronic Acid/chemistry , Mesenchymal Stem Cells/cytology , Animals , Cell Movement , Disease Progression , Extracellular Matrix/metabolism , Fibroblast Growth Factors/metabolism , Fibrosarcoma/pathology , Glycoproteins/metabolism , Humans , Inflammation , Insulin-Like Growth Factor I/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Mice , Neovascularization, Pathologic , Protein Binding , Proteoglycans/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism
6.
Biomed Res Int ; 2014: 124321, 2014.
Article in English | MEDLINE | ID: mdl-25140302

ABSTRACT

The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed.


Subject(s)
Breast Neoplasms/genetics , Carcinogenesis/genetics , Cell Movement/genetics , Proteoglycans/genetics , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Proteoglycans/metabolism , Signal Transduction/genetics , Tumor Microenvironment
7.
Biomed Res Int ; 2014: 606458, 2014.
Article in English | MEDLINE | ID: mdl-25126569

ABSTRACT

Collagen VI and hyaluronan are widely distributed extracellular matrix macromolecules that play a crucial role in tissue development and are highly expressed in cancers. Both hyaluronan and collagen VI are upregulated in breast cancer, generating a microenvironment that promotes tumour progression and metastasis. A growing number of studies show that these two molecules are involved in inflammation and angiogenesis by recruiting macrophages and endothelial cells, respectively. Additionally, collagen VI induces epithelial-mesenchymal transition that is correlated to increased synthesis of hyaluronan in mammary cells. Hyaluronan has also a specific role in cellular functions that depends mainly on the size of the polymer, whereas the effect of collagen VI in tumour progression may be the result of the intact molecule or the C5 peptide of α3(VI) chain, known as endotrophin. Collectively, these findings strongly support the parallel role of these molecules in tumour progression and suggest that they may be used as prognostic factors for the breast cancer treatment.


Subject(s)
Breast Neoplasms/genetics , Collagen Type VI/genetics , Extracellular Matrix/genetics , Hyaluronic Acid/biosynthesis , Breast Neoplasms/pathology , Collagen Type VI/biosynthesis , Epithelial-Mesenchymal Transition/genetics , Extracellular Matrix/pathology , Female , Humans , Hyaluronic Acid/genetics , Hyaluronic Acid/metabolism , Inflammation/genetics , Inflammation/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology
8.
Biomed Res Int ; 2013: 929531, 2013.
Article in English | MEDLINE | ID: mdl-24083250

ABSTRACT

Fibrosarcomas are rare malignant mesenchymal tumors originating from fibroblasts. Importantly, fibrosarcoma cells were shown to have a high content and turnover of extracellular matrix (ECM) components including hyaluronan (HA), proteoglycans, collagens, fibronectin, and laminin. ECMs are complicated structures that surround and support cells within tissues. During cancer progression, significant changes can be observed in the structural and mechanical properties of the ECM components. Importantly, hyaluronan deposition is usually higher in malignant tumors as compared to benign tissues, predicting tumor progression in some tumor types. Furthermore, activated stromal cells are able to produce tissue structure rich in hyaluronan in order to promote tumor growth. Key biological roles of HA result from its interactions with its specific CD44 and RHAMM (receptor for HA-mediated motility) cell-surface receptors. HA-receptor downstream signaling pathways regulate in turn cellular processes implicated in tumorigenesis. Growth factors, including PDGF-BB, TGFß2, and FGF-2, enhanced hyaluronan deposition to ECM and modulated HA-receptor expression in fibrosarcoma cells. Indeed, FGF-2 through upregulation of specific HAS isoforms and hyaluronan synthesis regulated secretion and net hyaluronan deposition to the fibrosarcoma pericellular matrix modulating these cells' migration capability. In this paper we discuss the involvement of hyaluronan/RHAMM/CD44 mediated signaling in the insidious pathways of fibrosarcoma progression.


Subject(s)
Disease Progression , Extracellular Matrix Proteins/metabolism , Fibrosarcoma/metabolism , Fibrosarcoma/pathology , Hyaluronan Receptors/metabolism , Hyaluronic Acid/metabolism , Carcinogenesis/metabolism , Carcinogenesis/pathology , Humans , Protein Binding
9.
J Biol Chem ; 286(44): 38509-38520, 2011 Nov 04.
Article in English | MEDLINE | ID: mdl-21914806

ABSTRACT

Hyaluronan (HA) modulates key cancer cell functions through interaction with its CD44 and receptor for hyaluronic acid-mediated motility (RHAMM) receptors. HA was recently found to regulate the migration of fibrosarcoma cells in a manner specifically dependent on its size. Here, we investigated the effect of HA/RHAMM signaling on the ability of HT1080 fibrosarcoma cells to adhere onto fibronectin. Low molecular weight HA (LMWHA) significantly increased (p ≤ 0.01) the adhesion capacity of HT1080 cells, which high molecular weight HA inhibited. The ability of HT1080 RHAMM-deficient cells, but not of CD44-deficient ones, to adhere was significantly decreased (p ≤ 0.001) as compared with control cells. Importantly, the effect of LMWHA on HT1080 cell adhesion was completely attenuated in RHAMM-deficient cells. In contrast, adhesion of RHAMM-deficient cells was not sensitive to high molecular weight HA treatment, which identifies RHAMM as a specific conduit of the LMWHA effect. Western blot and real time-PCR analyses indicated that LMWHA significantly increased RHAMM transcript (p ≤ 0.05) and protein isoform levels (53%, 95 kDa; 37%, 73 kDa) in fibrosarcoma cells. Moreover, Western blot analyses showed that LMWHA in a RHAMM-dependent manner enhanced basal and adhesion-dependent ERK1/2 and focal adhesion kinase (FAK) phosphorylation in HT1080 cells. Utilization of a specific ERK1/2 inhibitor completely inhibited (p ≤ 0.001) LMWHA-dependent adhesion, suggesting that ERK1/2 is a downstream effector of LMWHA/RHAMM signaling. Likewise, the utilization of the specific ERK1 inhibitor resulted in a strong down-regulation of FAK activation in HT1080 cells, which identifies ERK1/2 as a FAK upstream activator. In conclusion, our results suggest that RHAMM/HA interaction regulates fibrosarcoma cell adhesion via the activation of FAK and ERK1/2 signaling pathways.


Subject(s)
Extracellular Matrix Proteins/chemistry , Gene Expression Regulation, Neoplastic , Hyaluronan Receptors/chemistry , Hyaluronic Acid/chemistry , Cell Adhesion , Cell Line, Tumor , Fibrosarcoma/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Weight , Oligosaccharides/chemistry , RNA, Small Interfering/metabolism , Signal Transduction
10.
Int Arch Allergy Immunol ; 150(4): 389-97, 2009.
Article in English | MEDLINE | ID: mdl-19571571

ABSTRACT

BACKGROUND: Asthmatics who smoke have decreased pulmonary mature dendritic cells (DCs). Chronic obstructive pulmonary disease (COPD) patients have an increased amount of pulmonary immature DCs. We hypothesized that healthy smokers and patients with COPD have decreased pulmonary mature DCs. METHODS: We identified sputum DCs expressing the maturation markers CD83 and DC-lysosome associated membrane protein (DC-LAMP) and DC subpopulations (i.e. myeloid and plasmacytoid DCs) by flow cytometry in healthy smokers before they entered a smoking cessation trial (n = 30), in the same smokers after 6 months of smoking cessation (n = 11) and in COPD patients (n = 28, 14 current and 14 ex-smokers). 12 healthy never-smokers served as controls. DC numbers were expressed as percentage of total sputum CD45(+) leukocytes. RESULTS: CD83(+) and DC-LAMP(+) mature DCs were decreased in healthy smokers before they ceased smoking compared to after (p = 0.003 and p = 0.049, respectively) and in smokers before smoking cessation compared to never-smokers (p = 0.027 and p = 0.028, respectively). COPD patients, both current and ex-smokers, showed decreased CD83(+) mature DCs compared to never-smokers and smokers after cessation (p = 0.042 and p = 0.004, respectively). CONCLUSIONS: Cigarette smoking and COPD per se are associated with a decrease in pulmonary mature DCs. We speculate that this reduction is involved in the immunopathogenesis of smoking-related respiratory disorders, such as COPD.


Subject(s)
Antigens, Differentiation/metabolism , Dendritic Cells/metabolism , Pulmonary Disease, Chronic Obstructive/immunology , Smoking/immunology , Sputum/immunology , Adult , Aged , Antigens, CD/biosynthesis , Antigens, Differentiation/immunology , Cell Count , Dendritic Cells/immunology , Dendritic Cells/pathology , Female , Humans , Immunoglobulins/biosynthesis , Immunomodulation , Leukocyte Common Antigens/biosynthesis , Lysosomal Membrane Proteins/biosynthesis , Male , Membrane Glycoproteins/biosynthesis , Middle Aged , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/prevention & control , Smoking/adverse effects , Smoking/pathology , Smoking/physiopathology , Smoking/therapy , Smoking Cessation , Sputum/cytology , CD83 Antigen
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