Publications by authors named "Alfred K Lam"

97 Publications

Dataset for the reporting of carcinoma of the oesophagus in resection specimens: recommendations from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 May 13. Epub 2021 May 13.

Department of Pathology, Radboud University Medical Centre, 6500, Nijmegen, the Netherlands. Electronic address:

Background And Objectives: A standardised dataset for oesophageal carcinoma pathology reporting was developed based on the approach of the International Collaboration on Cancer Reporting (ICCR) for the purpose of improving cancer patient outcomes and international benchmarking in cancer management.

Materials And Methods: The ICCR convened a multidisciplinary international expert panel to identify the best evidence-based clinical and pathological parameters for inclusion in the dataset for oesophageal carcinoma. The dataset incorporated the current edition of the World Health Organization Classification of Tumours of the Digestive System, and Tumour-Node-Metastasis (TNM) staging systems.

Results: The scope of the dataset encompassed resection specimens of the oesophagus and oesophagogastric junction with tumour epicentre ≤20 millimetres into the proximal stomach. Core reporting elements included information on neoadjuvant therapy, operative procedure used, tumour focality, tumour site, tumour dimensions, distance of tumour to resection margins, histological tumour type, presence and type of dysplasia, tumour grade, extent of invasion in the oesophagus, lymphovascular invasion, response to neoadjuvant therapy, status of resection margin, ancillary studies, lymph node status, distant metastases and pathological staging. Additional non-core elements considered useful to report included clinical information, specimen dimensions, macroscopic appearance of tumour, and coexistent pathology.

Conclusions: This is the first international peer-reviewed structured reporting dataset for surgically resected specimens of the oesophagus. The ICCR carcinoma of the oesophagus dataset is recommended for routine use globally and is a valuable tool to support standardised reporting, to benefit patient care by providing diagnostic and prognostic best-practice parameters.
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http://dx.doi.org/10.1016/j.humpath.2021.05.003DOI Listing
May 2021

VEGF-A/VEGF-B/VEGF-C expressions in non-hereditary, non-metastatic phaeochromocytoma.

Histol Histopathol 2021 03 18:18329. Epub 2021 Mar 18.

School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Vascular endothelial growth factor (VEGF) is important in pathogenesis of different cancers. The aim of this study is to investigate the relationships between different VEGFs and clinicopathological factors in patients with phaeochromocytomas. Twenty patients (10 men; 10 women) with non-hereditary, non-metastatic phaeochromocytomas were examined for VEGF mRNA expressions by polymerase chain reaction. The expressions were correlated with the clinical and pathological factors of the patients. In addition, mouse double minute 2 (MDM2) expression in these tumours were studied by immunohistochemistry. High expressions of VEGF-A, VEGF-B, and VEGF-C mRNA were detected in 11 (55%), 9 (45%), and 9 (45%) of the tumours respectively. High expression of VEGF-A in phaeochromocytomas was significantly correlated with the tumour size (p=0.025) but did not correlate with patients' age, gender, and tumour laterality. Besides, there was a trend of VEGF-A expression correlated with MDM2 expression (p = 0.064). On the other hand, expressions of VEGF-B and VEGF-C were not significantly correlated with tumour size, patients' age, gender, tumour laterality, and MDM2 expression. In addition, high expressions of VEGF-B and VEGF-A were associated with increase of tumour size (p = 0.042). Co-expression of different VEGFs did not correlate with MDM2 expression. To conclude, there is a role for VEGF-A/VEGF-B/VEGF-C in the pathogenesis of non-hereditary, non-metastatic phaeochromocytomas.
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http://dx.doi.org/10.14670/HH-18-329DOI Listing
March 2021

Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas.

Front Oncol 2020 16;10:598957. Epub 2021 Feb 16.

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia.

Cancer stem cells (CSCs) in esophageal cancer have a key role in tumor initiation, progression and therapy resistance. Novel therapeutic strategies to target CSCs are being tested, however, more in-depth research is necessary. Eradication of CSCs can result in successful therapeutic approaches against esophageal cancer. Recent evidence suggests that targeting signaling pathways, miRNA expression profiles and other properties of CSCs are important strategies for cancer therapy. Wnt/β-catenin, Notch, Hedgehog, Hippo and other pathways play crucial roles in proliferation, differentiation, and self-renewal of stem cells as well as of CSCs. All of these pathways have been implicated in the regulation of esophageal CSCs and are potential therapeutic targets. Interference with these pathways or their components using small molecules could have therapeutic benefits. Similarly, miRNAs are able to regulate gene expression in esophageal CSCs, so targeting self-renewal pathways with miRNA could be utilized to as a potential therapeutic option. Moreover, hypoxia plays critical roles in esophageal cancer metabolism, stem cell proliferation, maintaining aggressiveness and in regulating the metastatic potential of cancer cells, therefore, targeting hypoxia factors could also provide effective therapeutic modalities against esophageal CSCs. To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.
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http://dx.doi.org/10.3389/fonc.2020.598957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921694PMC
February 2021

Molecular Pathology of Poorly Differentiated and Anaplastic Thyroid Cancer: What Do Pathologists Need to Know?

Endocr Pathol 2021 Mar 4;32(1):63-76. Epub 2021 Feb 4.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna School of Medicine, Bologna, Italy.

The molecular characterization of poorly and anaplastic thyroid carcinomas has been greatly improved in the last years following the advent of high throughput technologies. However, with special reference to genomic data, the prevalence of reported alterations is partly affected by classification criteria. The impact of molecular pathology in these tumors is multifaceted and bears diagnostic, prognostic, and predictive implications although its use in the clinical practice is not completely assessed. Genomic profiling data claim that genetic alterations in poorly differentiated and anaplastic thyroid carcinomas include "Early" and "Late" molecular events, which are consistent with a multi-step model of progression. "Early" driver events are mostly RAS and BRAF mutations, whereas "Late" changes include above all TP53 and TERT promoter mutations, as well as dysregulation of gene involved in the cell cycle, chromatin remodeling, histone modifications, and DNA mismatch repair. Gene fusions are rare but represent relevant therapeutic targets. Epigenetic modifications are also playing a relevant role in poorly differentiated and anaplastic thyroid carcinomas, with altered regulation of either genes by methylation/deacetylation or non-coding RNAs. The biological effects of epigenetic modifications are not fully elucidated but interfere with a wide spectrum of cellular functions. From a clinical standpoint, the combination of genomic and epigenetic data shows that several molecular alterations affect druggable cellular pathways in poorly differentiated and anaplastic thyroid carcinomas, although the clinical impact of molecular typing of these tumors in terms of predictive biomarker testing is still under exploration.
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http://dx.doi.org/10.1007/s12022-021-09665-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960587PMC
March 2021

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.

Theranostics 2021 1;11(6):2722-2741. Epub 2021 Jan 1.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.

: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). : Reverse phase protein array analysis was used to identify activated signaling pathways in -overexpressing cells. Chemokine array was used to identify differentially secreted factors from -overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. : and experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. -knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. : This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.
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http://dx.doi.org/10.7150/thno.49547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806492PMC
January 2021

What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?

Endocr Pathol 2021 Mar 12;32(1):134-153. Epub 2021 Jan 12.

Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype-phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype-phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.
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http://dx.doi.org/10.1007/s12022-020-09658-7DOI Listing
March 2021

CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice.

PLoS One 2021 7;16(1):e0223288. Epub 2021 Jan 7.

School of Medical Sciences, Griffith University, Gold Coast, Queensland, Australia.

Gene-editing has raised the possibility of being able to treat or cure cancers, but key challenges remain, including efficient delivery, in vivo efficacy, and its safety profile. Ideal targets for cancer therapy are oncogenes, that when edited, cause cell death. Here, we show, using the human papillomavirus (HPV) type 16 cancer cell line TC1, that CRISPR/Cas9 targeting the E7 oncogene and packaged in PEGylated liposomes cleared established tumours in immunocompetent mice. Treatment caused no significant toxicity in the spleen or liver. An ideal therapeutic outcome would be the induction of an immunogenic cell death (ICD), such that recurrent tumours would be eliminated by the host immune system. We show here for the first time that CRISPR/Cas9-mediated cell death via targeting E7 did not result in ICD. Overall, our data show that in vivo CRISPR/Cas targeting of oncogenes is an effective treatment approach for cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790238PMC
April 2021

Second primary malignancies in patients with papillary thyroid carcinoma after effect of post-chernobyl irradiation: A risk analysis of more than two decades of observations.

Cancer Epidemiol 2021 02 28;70:101860. Epub 2020 Nov 28.

School of Medicine, Griffith University, Gold Coast, QLD, 4222, Australia. Electronic address:

Background: Second primary malignancy in patients with papillary thyroid carcinoma after Chernobyl accident is an emerging problem. The aims of the study are to investigate the rates and distribution of second primary malignant tumours in Belarus survivors of post-Chernobyl papillary thyroid carcinoma and the cumulative rate of developing a second primary malignancy in a group of patients with metachronous second primaries.

Methods: Patients aged 18 or younger at the time of Chernobyl accident who were diagnosed with papillary thyroid carcinoma after 1986 were identified from the Belarus Cancer Registry. The clinical and demographic of these patients were analysed to correlate with the factors for the development of secondary primary cancer.

Results: Secondary primary cancer was detected in 1.8 % (119 of 6559) of the patients with papillary thyroid carcinoma. The cumulative incidence tended to rise with increasing age of the cohort and varied depending on the sex of patients. In female patients, breast carcinoma and genital tract carcinomas prevailed, in men patients - lymphoma/ leukaemia and the alimentary tract malignancies predominated. A significant excess risk was revealed for breast carcinoma in females, colon carcinoma in males, and the urinary system carcinomas in males (absolute excess risk [AER] = 3.23, 3.01 and 2.17 correspondingly). Overall, our results pointed to the increased risk of new solid primaries in females, males and both genders (AER = 3.31, 7.19, 4.28 correspondingly) as well as increase risk of lymphoid/hematopoietic malignancies in females and both genders (AER = 1.24) and leukaemia in male patients (AER = 1.45).

Conclusion: Patients with papillary thyroid carcinoma after Chernobyl accident are at risk of secondary primary malignancy. Awareness and screening of secondary cancer is needed for patients with papillary thyroid carcinoma after Chernobyl accident.
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http://dx.doi.org/10.1016/j.canep.2020.101860DOI Listing
February 2021

Roles of Non-Coding RNAs on Anaplastic Thyroid Carcinomas.

Cancers (Basel) 2020 Oct 28;12(11). Epub 2020 Oct 28.

School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia.

Anaplastic thyroid cancer (ATC) remains as one of the most aggressive human carcinomas with poor survival rates in patients with the cancer despite therapeutic interventions. Novel targeted and personalized therapies could solve the puzzle of poor survival rates of patients with ATC. In this review, we discuss the role of non-coding RNAs in the regulation of gene expression in ATC as well as how the changes in their expression could potentially reshape the characteristics of ATCs. A broad range of miRNA, such as miR-205, miR-19a, miR-17-3p and miR-17-5p, miR-618, miR-20a, miR-155, etc., have abnormal expressions in ATC tissues and cells when compared to those of non-neoplastic thyroid tissues and cells. Moreover, lncRNAs, such as H19, Human leukocyte antigen (HLA) complex P5 (HCP5), Urothelial carcinoma-associated 1 (UCA1), Nuclear paraspeckle assembly transcript 1 (NEAT1), etc., participate in transcription and post-transcriptional regulation of gene expression in ATC cells. Dysregulations of these non-coding RNAs were associated with development and progression of ATC by modulating the functions of oncogenes during tumour progression. Thus, restoration of the abnormal expression of these miRNAs and lncRNAs may serve as promising ways to treat the patients with ATC. In addition, siRNA mediated inhibition of several oncogenes may act as a potential option against ATC. Thus, non-coding RNAs can be useful as prognostic biomarkers and potential therapeutic targets for the better management of patients with ATC.
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http://dx.doi.org/10.3390/cancers12113159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693255PMC
October 2020

Molecular Deregulation of in the Pathogenesis of Esophageal Squamous Cell Carcinoma.

Front Oncol 2020 11;10:1534. Epub 2020 Sep 11.

School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.

Endothelial PAS domain-containing protein 1 (EPAS1) is an angiogenic factor and its implications have been reported in many cancers but not in esophageal squamous cell carcinoma (ESCC). Herein, we aim to examine the genetic and molecular alterations, clinical implications, and functional roles of in ESCC. High-resolution melt-curve analysis and Sanger sequencing were used to detect mutations in sequence. DNA number changes and mRNA expressions were analyzed by polymerase chain reaction. functional assays were used to study the impact of EPAS1 on cellular behaviors. Overall, 7.5% ( = 6/80) of patients with ESCC had mutations in , and eight novel variants (c.1084C>T, c.1099C>A, c.1145_1145delT, c.1093C>G, c.1121T>G, c.1137_1137delG, c.1135_1136insT, and c.1091_1092insT) were detected. Among these mutations, four were frameshift (V382Gfs12, A381Lfs13, K379Ifs6, and K364Nfs12) mutations and showed the potential of non-sense-mediated mRNA decay (NMD) in computational analysis. The majority of patients showed molecular deregulation of [45% ( = 36/80) DNA amplification, 42.5% ( = 34/80) DNA deletion, as well as 53.7% ( = 43/80) high mRNA expression, 20% ( = 16/80) low mRNA expression]. These alterations of were associated with tumor location and T stages. Patients with stage III ESCC having DNA amplification had poorer survival rates in comparison to DNA deletion ( = 0.04). In addition, suppression of in ESCC cells showed reduced proliferation, wound healing, migration, and invasion in comparison to that of control cells. Thus, the molecular and functional studies implied that plays crucial roles in the pathogenesis of ESCC and has the potential to be used as a prognostic marker and as a therapeutic target.
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http://dx.doi.org/10.3389/fonc.2020.01534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518048PMC
September 2020

Data set for reporting carcinoma of the thyroid: recommendations from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 Apr 10;110:62-72. Epub 2020 Sep 10.

University of Sydney, Sydney, New South Wales, 2006, Australia; Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

Thyroid cancer therapy is increasingly tailored to patients' risk of recurrence and death, placing renewed importance on pathologic parameters. The International Collaboration on Cancer Reporting (ICCR), an organization promoting evidence-based, internationally agreed-upon standardized pathology data sets, is the ideal conduit for the development of a pathology reporting protocol aimed at improving the care of patients with thyroid carcinomas. An international expert panel reviewed each element of thyroid pathology reporting. Recommendations were made based on the most recent literature and expert opinion.The data set uses the most recent World Health Organization (WHO) classification for the purpose of a more clinically and prognostically relevant nomenclature. One example is the restriction of the term minimally invasive follicular carcinoma to tumors with capsular invasion only. It reinforces the already established criteria for blood vessel invasion adopted by the most recent WHO classification and Armed Forces Institute of Pathology fascicle. It emphasizes the importance of the extent of blood vessel invasion and extrathyroid extension to better stratify patients for appropriate therapy. It is the first data set that requires pathologists to use the more recently recognized prognostically powerful parameters of mitotic activity and tumor necrosis. It highlights the importance of assessing nodal disease volume in predicting the risk of recurrence.The ICCR thyroid data set provides the tools to generate a report that will guide patient treatment in a more rational manner aiming to prevent the undertreatment of threatening malignancies and spare patients with indolent tumors the morbidity of unnecessary therapy. We recommend its routine use internationally for reporting thyroid carcinoma histology.
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http://dx.doi.org/10.1016/j.humpath.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943644PMC
April 2021

International Histopathology Consensus for Unilateral Primary Aldosteronism.

J Clin Endocrinol Metab 2021 Jan;106(1):42-54

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Germany.

Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA).

Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals.

Patients And Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists.

Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists.

Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.
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http://dx.doi.org/10.1210/clinem/dgaa484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765663PMC
January 2021

Diagnosis of digestive system tumours.

Int J Cancer 2021 Mar 19;148(5):1040-1050. Epub 2020 Nov 19.

WHO Classification of Tumours Group, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France.

The WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.
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http://dx.doi.org/10.1002/ijc.33210DOI Listing
March 2021

The Roles of Cancer Stem Cells and Therapy Resistance in Colorectal Carcinoma.

Cells 2020 06 3;9(6). Epub 2020 Jun 3.

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia.

Cancer stem cells (CSCs) are the main culprits involved in therapy resistance and disease recurrence in colorectal carcinoma (CRC). Results using cell culture, animal models and tissues from patients with CRC suggest the indispensable roles of colorectal CSCs in therapeutic failure. Conventional therapies target proliferating and mature cancer cells, while CSCs are mostly quiescent and poorly differentiated, thereby they can easily survive chemotherapeutic insults. The aberrant activation of Wnt/β-catenin, Notch, Hedgehog, Hippo/YAP (Yes-associated protein) and phosphatidylinositol 3-kinase/protein kinase B facilitates CSCs with excessive self-renewal and therapy resistance property in CRC. CSCs survive the chemo-radiotherapies by escaping therapy mediated DNA damage via altering the cell cycle checkpoints, increasing DNA damage repair capacity and by an efficient scavenging of reactive oxygen species. Furthermore, dysregulations of miRNAs e.g., miR-21, miR-93, miR-203, miR-215, miR-497 etc., modulate the therapeutic sensitivity of colorectal CSCs by regulating growth and survival signalling. In addition, a reversible quiescent G state and the re-entering cell cycle capacity of colorectal CSCs can accelerate tumour regeneration after treatment. Moreover, switching to favourable metabolic signatures during a therapeutic regimen will add more complexity in therapeutic outcomes against CSCs. Therapeutic strategies targeting these underlying mechanisms of CSCs' therapy resistance could provide a promising outcome, however, deep understanding and concerted research are necessary to design novel therapies targeting CSCs. To conclude, the understanding of these mechanisms of CSC in CRC could lead to the improved management of patients with CRC.
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http://dx.doi.org/10.3390/cells9061392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348976PMC
June 2020

Gastrointestinal tissue-based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours.

Histopathology 2020 Sep 4;77(3):340-350. Epub 2020 Jul 4.

Precision Medicine Centre of Excellence, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy-to-use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn.
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http://dx.doi.org/10.1111/his.14120DOI Listing
September 2020

Cancer risks along the disease trajectory in antineutrophil cytoplasmic antibody associated vasculitis.

Clin Rheumatol 2020 Sep 26;39(9):2501-2513. Epub 2020 Mar 26.

School of Medicine, Griffith University, Gold Coast, Queensland, 4222, Australia.

This review appraises the current literature on carcinogenic risks in anti-neutrophilic cytoplasmic autoantibody (ANCA) associated vasculitis (AAV). Patients with AAV are often at increased risk of developing non-melanoma skin carcinomas (NMSCs), haematological malignancies, bladder, breast, lung, prostate, and colorectal carcinomas. Reported cancer incidence in these patients ranged from 10 to 26%. Cancer risks at the time of diagnosis of AAV and disease outcomes along the trajectory of AAV that may lead to chronic kidney disease (CKD); dialysis and transplantation are summarized. Inherent carcinogenic risks as part of immunosuppressive treatment in AAV are further detailed with considerations on specific malignancy risks of therapeutic agents used. Challenges that contribute to malignancy risk include a high relapse rate of AAV and prolonged exposure to immunosuppressants. The incidence of malignancy increases significantly after 5 years of immunosuppressant exposure though risks in the earlier years have also been described. Following renal transplantation, there is limited information available on risk of malignancy. Thoughtful use of immunosuppressants, modification of lifestyle, and environmental factors, as well as adopting appropriate cancer screening will likely influence malignancy risk in individuals with AAV.
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http://dx.doi.org/10.1007/s10067-020-05055-xDOI Listing
September 2020

Immunohistochemistry for Protein Detection in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:279-294

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Immunohistochemistry is the identification of a cell protein by a specific antibody targeting that protein. It is the most common ancillary test to study the pathology of cancer. Immunohistochemical protein markers are used to differentiate poorly differentiated squamous cell carcinoma from poorly differentiated adenocarcinoma or neuroendocrine carcinomas. They could be used to identify and type the carcinoma in metastatic locations. Importantly, immunodetection of markers also helps in prediction of response to therapies as well as assessing the different biomarkers related to the pathogenesis and clinical behavior of esophageal squamous cell carcinoma. Successful application of the immunochemistry depends on understanding the mechanisms and principles as well as the limitations of the procedure. Automation of the procedure by different models of automatic stainers is widely used in diagnostic laboratories. The use of autostainers streamlines the workflows and certainly reduces the labor, time, and cost of using immunohistochemistry in clinical and research settings.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_21DOI Listing
March 2021

Immunoblotting in Detection of Tumor-Associated Antigens in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:269-277

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Tumor-associated antigens (TAAs) can be used as cancer markers and as signposts of therapeutic targets since their inimitable expression in cancer or significant overexpression in esophageal squamous cell carcinoma (ESCC) correlates with the initiation and progression of the diseases. Immunoblotting, also known as Western blotting or protein blotting, is a core technique in cell and molecular biology to detect proteins and glycoproteins. The technique allows detection of TAAs from complex protein samples such as in serum, aspirate, or solid tumor homogenate. In the process, proteins are separated according to the molecular weight. They were visualized within a gel matrix and then transferred to a supporting membrane. Finally, they are probed for binding with corresponding antibodies and identified the target proteins. Herein, we describe the Western blots analysis to detect protein or glycoprotein in samples from patients with esophageal squamous cell carcinoma (ESCC) or cells derived from ESCC.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_20DOI Listing
March 2021

Mass Spectrometry for Biomarkers Discovery in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:259-268

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Mass spectrometry-based proteomics analysis could categorize proteins and study their interactions in large scale in human cancers. By this method, many proteins are upregulated or downregulated in esophageal squamous cell carcinoma (ESCC) when compared to nonneoplastic esophageal mucosae. The method can also be used to identify novel, effective biomarkers for early diagnosis or predict prognosis of patients with ESCC. These changes are associated with different clinical and pathological parameters. Different biological matrices such as pathological tissue, body fluids, and cancer cell lines-based proteomics have widely been used. Herein, we described cell line-based label-free shotgun proteomics (in-solution tryptic digestion) to identify the protein biomarkers differently expressed in ESCC.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_19DOI Listing
March 2021

Roles of MicroRNAs in Esophageal Squamous Cell Carcinoma Pathogenesis.

Methods Mol Biol 2020 ;2129:241-257

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

MicroRNAs (miRNAs) are 20-22 nucleotides long single-stranded noncoding RNAs. They regulate gene expression posttranscriptionally by base pairing with the complementary sequences in the 3'-untranslated region of their targeted mRNA. Aberrant expression of miRNAs leads to alterations in the expression of oncogenes and tumor suppressors, thereby affecting cellular growth, proliferation, apoptosis, motility, and invasion capacity of gastrointestinal cells, including cells of esophageal squamous cell carcinoma (ESCC). Thus, alterations in miRNAs expression associated with the pathogenesis and progression of ESCC. In addition, expression profiles of miRNAs correlated with various clinicopathological factors, including pathological stages, histological differentiation, invasion, metastasis of cancer, as well as survival rates and therapy response of patients with ESCC. Consequently, expression profiles of miRNAs could be useful as diagnostic, prognostic, and prediction biomarkers in ESCC. Herein, we describe the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and microarray methods for detection and quantitate miRNAs in ESCC. In addition, we summarize the roles of miRNAs in ESCC pathogenesis, progression, and prognosis.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_18DOI Listing
March 2021

Genome Sequencing in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:217-240

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Technological advances in the form of next-generation sequencing allow sequencing of large numbers of different DNA sequences in a single/parallel reaction compared to conventional sequencing. It is a powerful tool which has enabled comprehensive characterization of esophageal squamous cell carcinoma. Whole-genome sequencing is the most comprehensive but expensive, whereas whole-exome sequencing is cost-effective, but it only works for the known genes. Thus, second-generation sequencing methods can provide a complete picture of the esophageal squamous cell carcinoma genome by detecting and discovering different type of alterations in the cancer which may lead to the development of effective diagnostic and therapeutic approaches for esophageal squamous cell carcinoma.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_17DOI Listing
March 2021

Liquid Biopsy for Investigation of Cancer DNA in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:203-215

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Early detection of cancer and the monitoring of cancer recurrence in treated patients are significant challenges in esophageal squamous cell carcinoma (ESCC). Liquid biopsy is the identification of tumor biomarkers from minimally invasive samples of biological fluids, including urine, blood, stool, saliva, or cerebrospinal fluid. Liquid biopsy offers a potential solution to the problems of detection and surveillance as DNA shed from cancer cells as cell-free DNA or in exosomes can be detected in body fluids. By detecting these DNAs, we can identify the presence of cancer-associated mutations for basic detection, as well as to obtain information on the recurrence and evolution of disease following initial treatment. These sources of information have the potential to significantly improve the management of patients with ESCC. In this chapter, we detail a method for the isolation of cell-free DNA from blood plasma and DNA associated with exosomes in blood from patients with esophageal squamous cell carcinomas.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_16DOI Listing
March 2021

Liquid Biopsy: Detection of Circulating Tumor Cells in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:193-202

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Circulating tumor cells (CTC) harvested in the blood of patients with esophageal squamous cell carcinoma (ESCC) are associated with certain clinical pathological parameters as well as patients' prognosis and response to chemoradiation. They are the source of distant metastases and their mechanisms of pathogenesis is complex. In recent years, advance in technologies has allowed scientists to detect, enumerate, and isolate these cells for further analysis and monitor the diseases progression in patients with cancer. There are a few methods available for the identification of individual CTC and clusters of CTCs (circulating tumor microemboli). The most commonly used is detection by immunomagnetic method. Although all these methods have limitations, they are helpful for understanding the pathogenesis of CTCs with potential applications in clinical managements in patients with ESCC.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_15DOI Listing
March 2021

Detention and Identification of Cancer Stem Cells in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:177-191

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Cancer stem cells (CSCs) are a small subpopulation of cells associated with cancer initiation, progression, metastasis, therapy resistant, and recurrence. In esophageal squamous cell carcinoma (ESCC), several cell surface and intracellular markers, for example, CD44, ALDH, Pygo2, MAML1, Twist1, Musashi1, side population (SP), CD271, and CD90, have been proposed to identify CSCs. In addition, stem cell markers such as ALDH1, HIWI, Oct3/4, ABCG2, SOX2, SALL4, BMI-1, NANOG, CD133, and podoplanin were associated with pathological stages of cancer, cancer recurrence, prognosis, and therapy resistance of patients with ESCC. Identification and isolation of CSCs could play an important part of improved cancer management regime in ESCC. Furthermore, CSCs may be used as the predictive tool for chemoradiotherapy response in ESCC. Different methods such as in vitro functional assays, cell sorting using various intracellular, and cell surface markers and xenotransplantation techniques are frequently used for the identification and isolation of CSCs in different cancers, including ESCC. However, none of these methods solely can guarantee complete isolation of CSC population. Therefore, a combination of methods is used for reliable detection and isolation of CSCs. Herein, we describe the identification and isolation of CSCs from ESCC cells by cell sorting after Hoechst 33342 staining followed by in vitro functional assays and in vivo mouse xenotransplantation techniques.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_14DOI Listing
March 2021

In Vitro Assays of Biological Aggressiveness of Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:161-175

Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Researchers are developing new techniques and technologies to determine the characteristic features for cancer progression, thereby identifying potential targets and therapeutics to interfere these hallmark processes of cancer pathogenesis. The transformative researches using these in vitro methods have enable researchers to design precision treatments of patients with esophageal squamous cell carcinoma (ESCC). These in vitro methods mainly include analysis of cell proliferation, cytotoxicity, colony formation, invasion, and migration in ESCC cells for analyzing manipulations affecting the biological behavior of ESCC. Because of these studies, important information on molecular mechanisms of different genes and proteins as well as result of therapeutic interventions are confirmed in ESCC.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_13DOI Listing
March 2021

Orthotopic Xenograft Mouse Model in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:149-160

Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

Orthotopic xenograft model recapitulates the faithful organ-specific microenvironment and facilitates analyses involving tumor-stromal interactions that are crucial for developing new-generation cancer therapy. Herein, we describe the detailed rationales and protocols of a versatile orthotopic xenograft model for esophageal squamous cell carcinoma.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_12DOI Listing
March 2021

Patient-Derived Xenograft and Mice Models in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:137-147

Kamford Health and Genetics Centre, Central, Hong Kong.

Mouse models are important in the study of pathogenesis, testing new treatment, and monitoring the progress of treatment in patients with esophageal squamous cell carcinoma (ESCC). The mice commonly used are immunosuppressed. The first category of models is for basic research and includes genetically engineered mouse models and carcinogen- or diet-induced mouse models. The second category of models involves either injection of cells with altered gene function related to pathogenesis of ESCC or ESCC cell lines. This method is commonly used and relatively inexpensive and simple to use. These cells commonly being subcutaneous injected in flank (subcutaneous xenograft model), tail vein, or peritoneum of immunodeficient mice. Direct implantation into the esophagus (orthotopic xenograft model) is also performed despite the cost and technical difficulties. The third category of mouse model is the patient-derived xenograft (PDX) model. In this model, ESCC tissues (instead of cell lines) removed from the patient are implanted into immunodeficient mice. This model appears promising for personalized medicine and of high resemblance to the nature of human ESCC, but there are many limitations for the use. It is likely to be used more in research in ESCC in the future. In this chapter, we detailed the preparation and experiments of PDX model from a patient with ESCC.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_11DOI Listing
March 2021

Use of Tissue Microarray in Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:119-135

Department of Biomedical Engineering, National Taiwan University, Taipei City, Taiwan.

Tissue microarray (TMA) is widely used for identifying the expression of markers in many tissues from patients with esophageal squamous cell carcinoma. The technology is mostly used in immunohistochemical studies to test the expression of markers and oncoproteins in signalling pathway as well as targeting proteins involved in therapies for esophageal squamous cell carcinoma. Appropriate use of TMA sections needs consideration of labor, planning, and expertise involved. For the best performance, it is important to design the layout of the TMA as well as use whole-slide scanning for interpretation of the TMA sections.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_10DOI Listing
March 2021

Whole-Slide Imaging of Esophageal Squamous Cell Carcinoma.

Methods Mol Biol 2020 ;2129:107-117

Cancer Molecular Pathology of School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Whole-slide imaging (WSI) contributes to medical education, collaboration, quality assurance, examination, and consultation in pathology. The images obtained from WSI are of high quality and could be stored indefinitely. In research involving esophageal squamous cell carcinoma, the combination of WSI and image processing program allows effective interpretations of expressions of various immunomarkers related to pathogenesis, prognosis, and response to therapy in tissue microarray sections. The operation and basic principles of whole-slide imaging of esophageal squamous cell carcinoma are also presented. Common use of WSI will occur with modifications of the whole-slide imaging scanners to adapt to the workflows in diagnostic and research laboratories.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_9DOI Listing
March 2021

Biobanking for Esophageal Squamous Cell Carcinoma.

Authors:
Alfred K Lam

Methods Mol Biol 2020 ;2129:95-105

Cancer Molecular Pathology of School of Medicine, Griffith University, Gold Coast, Queensland, Australia.

Biobanking is important and fundamental for research and personalized medicine in patients with esophageal squamous cell carcinoma. The process often involves prospective collection of surgically obtained tissues (tissue banking) as well as serial blood samples (liquid biopsies) from the patients with esophageal squamous cell carcinoma. Apart from frozen tissues, formalin-fixed paraffin-embedded tissues are important sources of translational research. Careful planning and selection of the region of the paraffin-embedded tissues will maximize the use of tissue for molecular studies. Both cancer and non-cancer samples (controls) could be collected. The success and sustainability of the process needs proper infrastructure, advanced planning, funding, and multidisciplinary collaborations. The understanding of the principles and issues are detrimental for the success of biobanking. The technical procedures involved are standardized, complex, and time-consuming and needs coordinated taskforce.
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http://dx.doi.org/10.1007/978-1-0716-0377-2_8DOI Listing
March 2021