Identification and Validation of Esophageal Squamous Cell Carcinoma Targets for Fluorescence Molecular Endoscopy

Dysplasia and intramucosal esophageal squamous cell carcinoma (ESCC) frequently go unnoticed with white-light endoscopy and, therefore, progress to invasive tumors. If suitable targets are available, fluorescence molecular endoscopy might be promising to improve early detection. Microarray expression data of patient-derived normal esophagus (n = 120) and ESCC samples (n = 118) were analyzed by functional genomic mRNA (FGmRNA) profiling to predict target upregulation on protein levels. The predicted top 60 upregulated genes were prioritized based on literature and immunohistochemistry (IHC) validation to select the most promising targets for fluorescent imaging. By IHC, GLUT1 showed significantly higher expression in ESCC tissue (30 patients) compared to the normal esophagus adjacent to the tumor (27 patients) (p < 0.001). Ex vivo imaging of GLUT1 with the 2-DG 800CW tracer showed that the mean fluorescence intensity in ESCC (n = 17) and high-grade dysplasia (HGD, n = 13) is higher (p < 0.05) compared to that in low-grade dysplasia (LGD) (n = 7) and to the normal esophagus adjacent to the tumor (n = 5). The sensitivity and specificity of 2-DG 800CW to detect HGD and ESCC is 80% and 83%, respectively (ROC = 0.85). We identified and validated GLUT1 as a promising molecular imaging target and demonstrated that fluorescent imaging after topical application of 2-DG 800CW can differentiate HGD and ESCC from LGD and normal esophagus.

Download Full-text

Does Daily Alcohol and/or Cigarette Consumption Cause Low-Grade Dysplasia, a Precursor of Esophageal Squamous Cell Carcinoma?

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2008.03.461 ◽

2008 ◽

Vol 67 (5) ◽

pp. AB187

Author(s):

Kazuhiro Kaneko ◽

Tomonori Yano ◽

Keiko Minashi ◽

Hiroaki Ikematsu ◽

Toshihiko Doi ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cigarette Consumption ◽

Low Grade ◽

Low Grade Dysplasia

Download Full-text

Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma

Human Mutation ◽

10.1002/humu.23027 ◽

2016 ◽

Vol 37 (9) ◽

pp. 942-954 ◽

Cited By ~ 31

Author(s):

Tara T. Doucet-O'Hare ◽

Reema Sharma ◽

Nemanja Rodić ◽

Robert A. Anders ◽

Kathleen H. Burns ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Clonal Expansion ◽

Normal Esophagus

Download Full-text

JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma

Cell Death and Disease ◽

10.1038/s41419-020-03279-y ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Catarina Macedo-Silva ◽

Vera Miranda-Gonçalves ◽

Ana Lameirinhas ◽

Joana Lencart ◽

Alexandre Pereira ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Hypoxic Conditions ◽

Histone Lysine ◽

Normal Esophagus ◽

Histone Lysine Demethylases

AbstractEsophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients’ survival.

Download Full-text

379 A STUDY TO UNRAVEL THE THERANOSTIC PARADIGM FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA IN INDIAN POPULATION

Diseases of the Esophagus ◽

10.1093/dote/doaa087.92 ◽

2020 ◽

Vol 33 (Supplement_1) ◽

Author(s):

R Rithvika ◽

V Pavithra ◽

S Rajendiran ◽

S Sundaram ◽

S Chandramohan ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Molecular Mechanisms ◽

Mutational Analysis ◽

Braf V600e ◽

Low Grade ◽

Middle Aged ◽

Female Patients

Abstract Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype in esophageal cancers (EC) and is one of the most aggressive cancers without effective therapy, Currently, Human papillomavirus (HPV) is suggested to be a potential risk factor for EC in addition to the classic predisposing factors, alcohol and tobacco, We have sought to investigate p16 a well-known biomarker for HPV and theranostic factors (EGFR & BRAF) that may have an impact on survival of ESCC. Methods We have analyzed 68 tissue biopsies which were histopathologically confirmed as ESCC. The paraffin embedded biopsies were subjected to immunohistochemistry (IHC) staining of EGFR and p16. The intensity of membrane staining for EGFR were scored as:0,1+,2+,3+, scores 2+ and 3+ were taken as over expression and score 1 as low expression. IHC for p16 was observed positive if it was brown colour in nucleus and cytoplasm. Then, mutational analysis for BRAF V600E was performed on a non biased data base by using PCR technique and confirming it through bidirectional Sanger sequencing. Results In total of 68 biopsies: Immunohistochemistry, - 56 biopsies (82.3%) overexpressed EGFR of which high grade ESCC’s showed greater expression than low grade. - 42 biopsies (61.7%) expressed p16 - 23 biopsies (33.8%) showing positivity for both p16 & EGFR thereby explaining p16 mediated EGFR upregulation Mutational analysis: Two middle aged female patients showed mutants: - Mutation of ACAGAAAAA was detected in V600E codon for one - Mutation of TCTGTATCA was detected in exon 11 of G466V for another - However IHC for p16 & EGFR of these two patients turned negative. Conclusion Our study reveals comprehensive mutational profile (EGFR, p16 and BRAF) on ESCC, shedding light on potential molecular mechanisms associated with its development and possible therapeutic regimens. Taken together with our findings, we propose a prospective study of a large sized population especially including middle aged female patients to further validate the role of this profile as indicators to unravel the theranostic values. To our knowledge this study is the first of it’s kind in India.

Download Full-text

Does Daily Alcohol and/or Cigarette Consumption Cause Low-grade Dysplasia, a Precursor of Esophageal Squamous Cell Carcinoma?

Journal of Clinical Gastroenterology ◽

10.1097/mcg.0b013e3181bb837a ◽

2010 ◽

Vol 44 (3) ◽

pp. 173-179 ◽

Cited By ~ 7

Author(s):

Kazuhiro Kaneko ◽

Yoshitaka Murakami ◽

Atsushi Katagiri ◽

Kazuo Konishi ◽

Yutaro Kubota ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cigarette Consumption ◽

Low Grade ◽

Low Grade Dysplasia

Download Full-text

MULTICENTER STUDY DESIGN OF THE EX VIVO EVALUATION OF ENDOCYTOSCOPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Digestive Endoscopy ◽

10.1111/j.1443-1661.2007.00739.x ◽

2007 ◽

Vol 19 (s1) ◽

pp. S153-S155 ◽

Cited By ~ 1

Author(s):

Manabu Muto ◽

Mitsuhiro Fujishiro ◽

Yoshitaka Sato ◽

Yasumasa Niwa ◽

Mitsuru Kaise ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Study Design ◽

Squamous Cell ◽

Multicenter Study ◽

Ex Vivo

Download Full-text

Potential and present limitation of endocytoscopy in the diagnosis of esophageal squamous-cell carcinoma: a multicenter ex vivo pilot study

Gastrointestinal Endoscopy ◽

10.1016/j.gie.2007.03.1044 ◽

2007 ◽

Vol 66 (3) ◽

pp. 551-555 ◽

Cited By ~ 23

Author(s):

Mitsuhiro Fujishiro ◽

Kaiyo Takubo ◽

Yoshitaka Sato ◽

Mitsuru Kaise ◽

Yasumasa Niwa ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Pilot Study ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Ex Vivo

Download Full-text

Comparison of Narrowband Imaging with Autofluorescence Imaging for Endoscopic Visualization of Superficial Squamous Cell Carcinoma Lesions of the Esophagus

Diagnostic and Therapeutic Endoscopy ◽

10.1155/2012/507597 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Haruhisa Suzuki ◽

Yutaka Saito ◽

Ichiro Oda ◽

Tsuyoshi Kikuchi ◽

Shinsuke Kiriyama ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

White Light ◽

Interobserver Agreement ◽

Autofluorescence Imaging ◽

White Light Endoscopy ◽

Narrowband Imaging ◽

Esophageal Carcinomas

Aim. To compare narrowband imaging (NBI) and autofluorescence imaging (AFI) endoscopic visualization for identifying superficial esophageal squamous cell carcinoma (SCC). Methods. Twenty-four patients with superficial esophageal carcinomas diagnosed at previous hospitals were enrolled in this study. Lesions were initially detected using white-light endoscopy and then observed with both NBI and AFI. Endoscopic images documented each method, and three endoscopists experienced in esophageal imaging retrospectively reviewed respective images of histologically confirmed esophageal SCCs. Images were assessed for quality in identifying superficial SCCs and rated as excellent, fair, or poor by the three reviewers with interobserver agreement calculated using kappa (κ) statistics. Results. Thirty-one lesions histologically confirmed as superficial esophageal SCCs were detected in 24 patients. NBI images of 27 lesions (87%) were rated as excellent, three as fair, and one as poor compared to AFI images of 19 lesions (61%) rated as excellent, 10 as fair and two as poor (P<0.05). Moderate interobserver agreement (κ=0.42, 95% CI 0.24–0.60) resulted in NBI while fair agreement (κ=0.35, 95% CI 0.18–0.51) was achieved using AFI. Conclusion. NBI may be more effective than AFI for visualization of esophageal SCC.

Download Full-text