SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract

doi:10.1016/j.humpath.2009.06.006

Human Pathology

Volume 40, Issue 12, December 2009, Pages 1768-1773

https://doi.org/10.1016/j.humpath.2009.06.006 Get rights and content

Summary

SOX2 is a high-mobility group box embryonic stem cell transcription factor that is expressed in the developing foregut and normal gastric epithelium and is downregulated in intestinal metaplasia of the stomach and esophagus. In addition, SOX2 colocalizes with p63 in the basal layer and plays a critical role in the maintenance of the stratified squamous epithelium of the esophagus. SOX2 expression in squamous cell carcinomas of the gastrointestinal tract has not been previously evaluated. The purpose of this study was to determine whether SOX2 is differentially expressed in squamous cell carcinomas versus adenocarcinomas of the esophagus and rectum/anal canal and to compare its expression to p63, cytokeratin 5/6, and CDX2. In total, 93 tumors were evaluated: 26 esophageal squamous cell carcinomas, 23 esophageal adenocarcinomas, 21 squamous cell carcinomas of the anal canal, and 23 rectal adenocarcinomas. SOX2 was expressed in 81% of esophageal squamous cell carcinomas and 91% of anal canal squamous cell carcinomas, compared to 13% and 17% of esophageal and rectal adenocarcinomas, respectively. p63 was expressed in 96% of esophageal squamous cell carcinomas and 100% of anal canal squamous cell carcinomas; the single squamous cell carcinoma negative for p63 was strongly positive for SOX2. Cytokeratin 5/6 was expressed in most esophageal and anal canal squamous cell carcinomas, but was also positive in 43% of esophageal adenocarcinomas and 13% of rectal adenocarcinomas. In summary, SOX2 is preferentially expressed in squamous cell carcinomas of the esophagus and anal canal compared to adenocarcinomas from these sites. SOX2 may be useful in an immunohistochemical panel to differentiate between squamous cell carcinomas and adenocarcinomas of the gastrointestinal tract.

Introduction

SOX2 is a high-mobility group box transcription factor involved in the maintenance of pluripotency and self-renewal in embryonic stem cells [1], [2], [3]. SOX2 has also been reported to play a critical role in several developmental processes, including neural stem cell specification and maintenance [4], [5] and lung morphogenesis [6], [7]. In the upper gastrointestinal (GI) tract, SOX2 is expressed in the developing foregut endoderm and is thought to play a role in establishing the boundary between the keratinized, squamous-lined esophagus and glandular hindstomach [8]. Reduced SOX2 levels in mouse embryo models are associated with esophageal atresia and other developmental esophageal abnormalities including the presence of luminal mucus-producing cells, ectopic expression of genes normally expressed in the glandular stomach, and reduced numbers of p63-positive basal cells [8].

In the stomach, SOX2 is expressed in normal foveolar epithelium, and reduced expression is associated with intestinal metaplasia and intestinal-type gastric adenocarcinoma (ACA) [9], [10]. In addition, SOX2 and CDX2 appear to show an inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia and in gastric-type versus intestinal-type ACA [10], [11]. In the lower GI tract, recent studies have suggested that SOX2 is not expressed in normal epithelium or in nonmucinous ACA [12]. SOX2 has not heretofore been examined in squamous cell carcinomas (SCC) of the GI tract.

For the surgical pathologist, differentiating between SCC and ACA of the esophagus and rectum/anal canal is usually straightforward based on histologic features; however, it can occasionally be problematic, particularly in the setting of poorly differentiated tumors and/or small biopsy specimens. Immunohistochemical markers often used in this context include CDX2, p63, and high-molecular-weight keratins such as cytokeratin 5/6 (CK5/6). Individual sensitivities and specificities are variable, and immunohistochemical panels are often used to improve accuracy. SOX2 expression has not been previously evaluated in SCC of the GI tract. Based on the postulated biological role of SOX2 in maintenance of the stratified squamous epithelium, we hypothesized that SOX2 may be differentially expressed in SCC versus ACA of the esophagus and rectum/anal canal.

In this study, we examine the expression of SOX2 in SCC and ACA of the esophagus and rectum/anal canal and compare its immunohistochemical profile with CDX2, p63, and CK5/6.

Section snippets

Materials and methods

A total of 93 formalin-fixed paraffin-embedded tumors were selected from the archives of the Brigham and Women's Hospital Department of Pathology from 2004 to 2008. Samples included endoscopically obtained mucosal biopsies and surgical resections of primary, untreated tumors. Four-micrometer-thick hematoxylin and eosin–stained sections were reviewed to confirm the diagnosis and grade/differentiation (well, moderate, or poor).

Antibodies, clones, dilutions, pretreatment conditions, and sources

Results

In nonneoplastic stratified squamous epithelium of both the anal canal and esophagus, SOX2 showed a similar expression pattern to that of p63, with the strongest expression in the basal layer and progressively diminished staining in the maturing superficial epithelium (data not shown). Results of immunohistochemical studies in carcinomas are summarized in Table 2, Table 3. SOX2 was expressed in 81% of esophageal SCC and 91% of anal canal SCC, compared to 13% and 17% of esophageal and rectal

Discussion

SOX2 belongs to a highly conserved family of high-mobility group box transcription factors with the sex-determining gene Sry as the founding member. Sox proteins are important factors in the regulation of embryonic development and determination of cell fate and maintenance [13]. SOX2 in particular, along with OCT3/4 and NANOG, plays a crucial role in the maintenance of embryonic stem cell pluripotency by regulating the expression of lineage commitment factors [1], [2], [3], [14], [15], [16].

References (24)

PevnyL. et al.
SOX genes and neural progenitor identity
Curr Opin Neurobiol
(2005)
GontanC. et al.
Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation
Dev Biol
(2008)
LefebvreV. et al.
Control of cell fate and differentiation by Sry-related high-mobility group box (Sox) transcription factors
Int J Biochem Cell Biol
(2007)
PeiD.
Regulation of pluripotency and reprogramming by transcription factors
J Biol Chem
(2009)
BoyerL.A. et al.
Core transcriptional regulatory circuitry in human embryonic stem cells
Cell
(2005)
GrahamV. et al.
SOX2 functions to maintain neural progenitor identity
Neuron
(2003)
Rodriguez-PinillaS.M. et al.
Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer
Mod Pathol
(2007)
ChenX. et al.
Multilayered epithelium in a rat model and human Barrett's esophagus: similar expression patterns of transcription factors and differentiation markers
BMC Gastroenterol
(2008)
BoianiM. et al.
Regulatory networks in embryo-derived pluripotent stem cells
Nat Rev Mol Cell Biol
(2005)
IvanovaN. et al.
Dissecting self-renewal in stem cells with RNA interference
Nature
(2006)

WangJ. et al.

A protein interaction network for pluripotency of embryonic stem cells

Nature

(2006)

EllisP. et al.

SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult

Dev Neuroscience

(2004)

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SOX2 and squamous cancers
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SOX2 is a pleiotropic nuclear transcription factor with major roles in stem cell biology and in development. Over the last 10 years SOX2 has also been implicated as a lineage-specific oncogene, notably in squamous carcinomas but also neurological tumours, particularly glioblastoma. Squamous carcinomas (SQCs) comprise a common group of malignancies for which there are no targeted therapeutic interventions. In this article we review the molecular epidemiological and laboratory evidence linking SOX2 with squamous carcinogenesis, explore in detail the multifaceted impact of SOX2 in SQC, describe areas of uncertainty and highlight areas for potential future research.
SOX2 in development and cancer biology
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The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.
Ultrasensitive microfluidic electrochemical immunosensor based on electrodeposited nanoporous gold for SOX-2 determination
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Several mutations in this gene have been associated with a severe malformation in the eye structure called anophthalmia. It has also been determined that ectopic expression of SOX-2 could be related to abnormal differentiation of colorectal cancer cells [5], as well as to overexpression in breast [6], ovarian [7], lung [8], esophageal [9], prostate [10], pancreatic [11], testicular [12], and skin/neck/head squamous cell carcinoma, among others [13,14]. Taking into account the issues mentioned above, the development of a sensitive, selective, fast, and portable device to detect SOX-2 in human serum samples is imperative.
An ultrasensitive and portable microfluidic electrochemical immunosensor for SOX-2 cancer biomarker determination was developed. The selectivity and sensitivity of the sensor were improved by modifying the microfluidic channel. This was accomplished through a physical-chemical treatment to produce a hydrophilic surface, with an increased surface to volume/ratio, where the anti-SOX-2 antibodies can be covalently immobilized. A sputtered gold electrode was used as detector and its surface was activated by using a dynamic hydrogen bubble template method. As a result, a gold nanoporous structure (NPAu) with outstanding properties, like high specific surface area, large pore volume, uniform nanostructure, good conductivity, and excellent electrochemical activity was obtained.
SOX-2 present in the sample was bound to the anti-SOX-2 immobilized in the microfluidic channel, and then was labeled with a second antibody marked with horseradish peroxidase (HRP-anti-SOX-2) like a sandwich immunoassay. Finally, an H₂O₂ + catechol solution was added, and the enzymatic product (quinone) was reduced on the NPAu electrode at +0.1 V (vs. Ag). The current obtained was directly proportional to the SOX-2 concentration in the sample. The detection limit achieved was 30 pg mL⁻¹, and the coefficient of variation was less than 4.75%. Therefore, the microfluidic electrochemical immunosensor is a suitable clinical device for in situ SOX-2 determination in real samples.
Unraveling cancer lineage drivers in squamous cell carcinomas
2020, Pharmacology and Therapeutics
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Studies using various pre-clinical GEMMs and cellular models have revealed pathways known to be important for squamous fate specification and differentiation, and provided unprecedented insights into carcinogenesis mechanisms and as well as putative therapeutic targets. As discussed above, SCCs exhibit a characteristic copy number alteration event, namely frequent co-amplification of numerous oncogenes at 3q26-3q28 (Bass et al., 2009; Freier et al., 2010; Hussenet et al., 2010; Long & Hornick, 2009; Maier et al., 2011; Yuan et al., 2010). Below, we review some of the known examples of SCC drivers residing within this region.
Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.
American registry of pathology expert opinions: Evaluation of poorly differentiated malignant neoplasms on limited samples – Gastrointestinal mucosal biopsies
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In addition, nearly half of lymphomas, including most diffuse large B-cell lymphomas, express p63, while p40 is always negative. CDX2 is expressed by 60–80% of esophageal adenocarcinomas, although, as a note of caution, it is co-expressed by up to 20% of esophageal (and anorectal) squamous cell carcinomas—though in squamous cell carcinomas expression tends to be limited in extent [11-13]. CDH17 is emerging as an alternative pan-GI tract adenocarcinoma marker, probably more sensitive than CDX2 [14].
This review reflects a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is part of a series of expert recommendations on topics encountered in daily practice. The authors, three pathologists with expertise in gastrointestinal tract pathology and immunohistochemistry, met on 30 July 2019 tasked with developing expert recommendations for evaluating poorly differentiated and undifferentiated malignant neoplasms encountered on mucosal biopsies of the gastrointestinal tract. We focused on esophageal, gastric, small intestinal, colorectal, and anal (i.e., tubal gut) samples. When faced with diagnostic uncertainty on the initial H&E, it is best to begin by trying to assign the broad tumor class with screening markers such as pankeratin, S100 protein or SOX10, and CD20 or CD45. Once a broad tumor class is established, more specific differentiation markers can be pursued (e.g., lineage-restricted transcription factors for adenocarcinoma; p40 for squamous cell carcinoma; chromogranin A and synaptophysin or INSM1 for neuroendocrine neoplasms). Every small biopsy containing tumor should be considered a potential molecular pathology sample; cutting extra unstained slides with this testing in mind is strongly encouraged.
The role of pluripotency factors to drive stemness in gastrointestinal cancer
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In addition to its fundamental role in the maintenance of embryonic stem cells, SOX2 is important during embryonic development of gastrointestinal organs: SOX2 is expressed in the developing foregut and gastric epithelium. SOX2 co-localizes with p63 in the basal layer of the esophagus and is critical in the maintenance of the stratified squamous epithelium, however it is down-regulated in intestinal metaplasias of the stomach and esophagus (Long and Hornick, 2009). In vitro, SOX2 expression promotes cell proliferation in esophageal squamous-cell carcinoma (Gen et al., 2013).
A better molecular understanding of gastrointestinal cancers arising either from the stomach, the pancreas, the intestine, or the liver has led to the identification of a variety of potential new molecular therapeutic targets. However, in most cases surgery remains the only curative option. The intratumoral cellular heterogeneity of cancer stem cells, bulk tumor cells, and stromal cells further limits straightforward targeting approaches. Accumulating evidence reveals an intimate link between embryonic development, stem cells, and cancer formation. In line, a growing number of oncofetal proteins are found to play common roles within these processes. Cancer stem cells share features with true stem cells by having the capacity to self-renew in a de-differentiated state, to generate heterogeneous types of differentiated progeny, and to give rise to the bulk tumor. Further, various studies identified genes in cancer stem cells, which were previously shown to regulate the pluripotency circuitry, particularly the so-called “Yamanaka-Factors” (OCT4, KLF4, SOX2, and c-MYC). However, the true stemness potential of cancer stem cells and the role and expression pattern of such pluripotency genes in various tumor cell types remain to be explored. Here, we summarize recent findings and discuss the potential mechanisms involved, and link them to clinical significance with a particular focus on gastrointestinal cancers.

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: Presented in part at the 98th Annual Meeting of the United States and Canadian Academy of Pathology (USCAP) in Boston, MA, March 7-13, 2009.

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Original contributionSOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract

Summary

Introduction

Section snippets

Materials and methods

Results

Discussion

Curr Opin Neurobiol

Dev Biol

Int J Biochem Cell Biol

J Biol Chem

Cell

Neuron

Mod Pathol

BMC Gastroenterol

Regulatory networks in embryo-derived pluripotent stem cells

Nat Rev Mol Cell Biol

Dissecting self-renewal in stem cells with RNA interference

Nature

A protein interaction network for pluripotency of embryonic stem cells

Nature

SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult

Dev Neuroscience

Original contribution
SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract