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  • 1
    Online Resource
    Online Resource
    Collagen Type XI Inhibits Lung Cancer-Associated Fibroblast Functions and Restrains the Integrin Binding Site Availability on Collagen Type I Matrix
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 19 ( 2022-10-03), p. 11722-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 19 ( 2022-10-03), p. 11722-
    Abstract: The tumor microenvironment, including cancer-associated fibroblast (CAF), plays an active role in non-small cell lung cancer (NSCLC) development and progression. We previously reported that collagen type XI and integrin α11, a collagen receptor, were upregulated in NSCLC; the latter promotes tumor growth and metastasis. We here explored the role of collagen type XI in NSCLC stroma. We showed that the presence of collagen type XI in collagen type I matrices inhibits CAF-mediated collagen remodeling and cell migration. This resulted in the inhibition of CAF-dependent lung-tumor cell invasion. Among the collagen receptors expressed on CAF, we determined that DDR2 and integrin α2β1, but not integrin α11β1, mediated the high-affinity binding to collagen type XI. We further demonstrated that collagen type XI restrained the integrin binding site availability on collagen type I matrices, thus limiting cell interaction with collagen type I. As a consequence, CAFs failed to activate FAK, p38 and Akt one hour after they interacted with collagen type I/XI. We concluded that collagen type XI may have a competitive negative feedback role on the binding of collagen type I to its receptors.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms231911722
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
    Online Resource
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    Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway
    MDPI AG ; 2018
    In:  Nutrients Vol. 10, No. 9 ( 2018-09-12), p. 1289-
    Details
    In: Nutrients, MDPI AG, Vol. 10, No. 9 ( 2018-09-12), p. 1289-
    Abstract: Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu10091289
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2518386-2
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  • 3
    Online Resource
    Online Resource
    Reflex ROS1 IHC Screening with FISH Confirmation for Advanced Non-Small Cell Lung Cancer—A Cost-Efficient Strategy in a Public Healthcare System
    MDPI AG ; 2021
    In:  Current Oncology Vol. 28, No. 5 ( 2021-08-25), p. 3268-3279
    Details
    In: Current Oncology, MDPI AG, Vol. 28, No. 5 ( 2021-08-25), p. 3268-3279
    Abstract: ROS1 rearrangements are identified in 1–2% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR/ALK/KRAS wildtype) testing initiated by pathologists and clinician-initiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    URL: Article
    DOI: 10.3390/curroncol28050284
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2270777-3
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  • 4
    Online Resource
    Online Resource
    LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 5 ( 2019-05-22), p. 705-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 5 ( 2019-05-22), p. 705-
    Abstract: Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells. Using cancer-associated fibroblast (CAF) with either a knockdown or overexpression of LOXL1, we demonstrated a role for LOXL1 in collagen matrix remodeling and collagen fiber alignment in vitro and in vivo in a NSCLC xenograft model. As a consequence of collagen reorganization in NSCLC tumor stroma, we showed that LOXL1 supported tumor growth and progression. Our findings demonstrate that stromal LOXL1, under regulation of integrin α11, is a determinant factor of NSCLC tumorigenesis and may be an interesting target in this disease.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11050705
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma
    MDPI AG ; 2020
    In:  Pharmaceuticals Vol. 13, No. 10 ( 2020-10-02), p. 289-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 13, No. 10 ( 2020-10-02), p. 289-
    Abstract: Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a 89Zr-labeled immunoconjugate—ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using 89Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph13100289
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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  • 6
    Online Resource
    Online Resource
    Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma
    MDPI AG ; 2021
    In:  Cancers Vol. 14, No. 1 ( 2021-12-31), p. 205-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 1 ( 2021-12-31), p. 205-
    Abstract: Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+ LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05–1.77, p = 0.018) and validated in NCI Director’s Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14–2.09, p = 0.0045). Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14010205
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 7
    Online Resource
    Online Resource
    Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts
    MDPI AG ; 2014
    In:  Cancers Vol. 6, No. 1 ( 2014-02-26), p. 459-471
    Details
    In: Cancers, MDPI AG, Vol. 6, No. 1 ( 2014-02-26), p. 459-471
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers6010459
    Language: English
    Publisher: MDPI AG
    Publication Date: 2014
    detail.hit.zdb_id: 2527080-1
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  • 8
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    Online Resource
    Somatic Alteration Burden Involving Non-Cancer Genes Predicts Prognosis in Early-Stage Non-Small Cell Lung Cancer
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 7 ( 2019-07-19), p. 1009-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 7 ( 2019-07-19), p. 1009-
    Abstract: The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients. From a small cohort of 36 NSCLC cases, we were able to identify somatic mutations and copy number alterations in 865 genes that contributed to patient overall survival. Simply, the number of altered genes (NAG) among these 865 genes was associated with longer disease-free survival (hazard ratio (HR) = 0.153, p = 1.48 × 10−4). The gene expression signature distinguishing patients with high/low NAG was also prognostic in three independent datasets. Patients with a high NAG could be further stratified based on the presence of immunogenic mutations, revealing a further subgroup of stage I NSCLC with even better prognosis (85% with 〉 5 years survival), and associated with cytotoxic T-cell expression. Importantly, 95% of the highly-altered genes lacked direct relation to cancer, but were implicated in pathways regulating cell proliferation, motility and immune response.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11071009
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 9
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    Online Resource
    Circulating miR-16-5p, miR-92a-3p, and miR-451a in Plasma from Lung Cancer Patients: Potential Application in Early Detection and a Regulatory Role in Tumorigenesis Pathways
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 8 ( 2020-07-27), p. 2071-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 8 ( 2020-07-27), p. 2071-
    Abstract: Background: Micro(mi)RNAs, potent gene expression regulators associated with tumorigenesis, are stable, abundant circulating molecules, and detectable in plasma. Thus, miRNAs could potentially be useful in early lung cancer detection. We aimed to identify circulating miRNA signatures in plasma from patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and to verify whether miRNAs regulate lung oncogenesis pathways. Methods: RNA isolated from 139 plasma samples (40 LUAD, 38 LUSC; 61 healthy/non-diseased individuals) were divided into discovery (38 patients; 21 controls for expression quantification using an 800-miRNA panel; Nanostring nCounter®) and validation (40 patients; 40 controls; TaqMan® RT-qPCR) cohorts. Elastic net, Maximizing-R-Square Analysis (MARSA), and C-Statistics were applied for miRNA signature identification. Results: When compared to healthy individuals, 580 of 606 deregulated miRNAs in LUAD and 221 of 226 deregulated miRNAs in LUSC had significantly increased levels. Among the 10 most significantly overexpressed miRNAs, 6 were common to patients with LUAD and LUSC. Further analysis identified three signatures composed of 12 miRNAs. Signatures included miRNAs commonly overexpressed in patient plasma. Enriched pathways included target genes modulated by three miRNAs in the C-Statistics signature: miR-16-5p, miR-92a-3p, and miR-451a. Conclusions: The 3-miRNA signature (miR-16-5p, miR-92a-3p, miR-451a) had high specificity (100%) and sensitivity (84%) to predict cancer (LUAD and LUSC). These miRNAs are predicted to modulate genes and pathways with known roles in lung tumorigenesis, including EGFR, K-RAS, and PI3K/AKT signaling, suggesting that the 3-miRNA signature is biologically relevant in adenocarcinoma and squamous cell carcinoma of the lung.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12082071
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 10
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    Online Resource
    Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults
    MDPI AG ; 2021
    In:  Current Oncology Vol. 28, No. 1 ( 2021-01-15), p. 523-548
    Details
    In: Current Oncology, MDPI AG, Vol. 28, No. 1 ( 2021-01-15), p. 523-548
    Abstract: The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency ( 〈 5%), and at a higher frequency ( 〉 80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    URL: Article
    DOI: 10.3390/curroncol28010053
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2270777-3
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