Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. It has been shown that gastric cancer may originate from adult gastric stem cells and that it contains a subpopulation of cancer cells with stem cell characteristics, which are linked to Helicobacter pylori infection, therapy resistance and metastasis. Thus, the identification of transcription factors and related signal transduction pathways that regulate stem cell maintenance and lineage allocation is attractive from a clinical standpoint in that it may provide targets for novel cell- or drug-based therapies. This chapter summarizes the role of several important stem cell factors in gastric cancer biology.
Keywords
- cancer stem cells
- gastric cancer
- SOX genes
- Helicobacter pylori
1. Introduction
Gastric adenocarcinoma (GC) is the second most common cause of cancer-related mortality in the world, with developing countries being the most affected regions [1, 2]. GC is a complex disease influenced by different environmental and genetic factors. Among them,
Gastric cancer accounts for around 10% of all new cancers (one million per year), and it is the second leading cause of cancer death globally (700,000 deaths per year). The prognosis of CG is very poor, with a survival rate below 30% at 5 years post diagnosis [1, 2]. It is usually asymptomatic or causes nonspecific symptoms at early stages. When symptoms appear, the cancer has usually reached an advanced stage and there is presence of metastasis, being this dissemination a main cause of the severe prognosis. GC-associated high mortality is the result of its silent nature and the extremely high heterogeneity exhibited between individuals and also within gastric tumors. This heterogeneity involves, at the molecular level, a broad variety of gene mutations, amplifications and/or expression alterations, diverse DNA methylation profiles and differences in the activation or inactivation of particular signaling pathways. Thus, in the last years there has been substantial progress in the elucidation of the genomic landscape of GC due to advances in high-throughput technologies and the effort of international consortiums. Consequently, gastric cancer has been recently reclassified and stratified into several distinct subtypes based on molecular and genetic/epigenetic alterations [5, 6]. In particular, GCs have been classified according to defined genetic signatures, the status of
It has been noticed that the incidence of GC has declined over time mostly in developed countries, due to improving living standards. However, and despite increasing knowledge and improvements in the standard of care, therapy resistance and metastasis remain the main causes of treatment failure and death in GC patients and GC as a disease remains a serious and significant social concern. Consequently, identifying the major GC drivers and the molecular and cellular mechanisms responsible for the GC heterogeneity and maintenance is crucial to understand the pathobiology of GC and establish optimal therapies that able to improve the prognosis of patients.
2. Cancer stem cells in gastric cancer
Several types of solid cancers, including gastric cancers, contain phenotypically and functionally heterogeneous cancer cells [8]. These cancers present a small subpopulation of cells that display characteristics similar to normal stem cells, including unlimited self-renewal, proliferation and multi-lineage differentiation. These cells are called cancer stem cells (CSCs), which are supposed to maintain long-term tumor growth, recurrence and chemotherapy resistance. The origin of gastric CSCs is not completely clear, but it has been observed that this subpopulation of cells can derive from the differentiated gastric epithelial cells, local progenitor cells in the gastric mucosa and bone marrow-derived cells (BMDCs) [9]. In line with this idea, chronic infection of C57BL/6 mice with
2.1. Regulators of gastric cancer stem cells
2.1.1. LGR5
The human leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a member of the G protein-coupled transmembrane receptor (GPCR) superfamily. LGR5 is a receptor for R-spondins that belong to the WNT signalling complex at the membrane level [15] and is also a target gene of this pathway [16]. LGR5 is overexpressed in a variety of human cancers, including tumors of the digestive tract such as colorectal [17] or gastric cancer [18–20], wherein it has been postulated as a CSC marker. LGR5 is an established stem cell marker of the intestine, and several studies on mice and humans have shown that LGR5-positive stem cells are the cells-of-origin of intestinal and colorectal cancer [21–27]. In the stomach, there are also increasing evidence postulating LGR5 as a stem cell and CSC marker. Thereby, LGR5 expression in gastric mucosa is almost restricted to a subset of cells located at the base of the pyloric glands, distribution that fits well with the multiple sites of the gastric cancer in humans [28]. Through
2.1.2. CD133
CD133 (also Prominin 1) is a pentaspan transmembrane glycoprotein present in embryonic epithelial structures, thought to function as an organizer of plasma membrane topology, and regulating the maintenance of the appropriate lipid composition within the plasma membrane [34]. CD133 has been presented as a marker of cancer stem cells in colon, pancreas, brain or lung cancer [35], yet its role in gastric CSCs is controversial. Several findings related to different aspects of gastric CSCs have been published in support of its role as a gastric CSC marker and regulator. In gastric cancer cell lines, CD133 silencing abrogates sphere formation capacity [36] and, consistently, CD133 has been found overexpressed in gastric sphere cultures [37, 38]. Noteworthy, a large number of publications show increased CD133 expression in human gastric cancer tissue respect to non-neoplastic gastric mucosa and highlight the prognostic significance of CD133, associating its overexpression with a big plethora of adverse clinic-pathological features, such as elevated cellular proliferation rates, high T stage, venous invasion, lymph node and distant metastasis, chemoresistance, recurrence, poor 5-year disease-free and overall survival and so on [37, 39–42]. According to this, studies performed in gastric cancer cell lines demonstrate that CD133-positive gastric cancer cells present a CSC phenotype, since they are more tumorigenic, more chemoresistant and exhibit higher migration or invasion capacities than CD133-negative cells [37, 38, 43]. However, some controversial findings have been published indicating that CD133 expression is not a
2.1.3. CD44
CD44 is a transmembrane glycoprotein expressed on leukocytes, endothelial cells, hepatocytes or gastric epithelial cells, which acts as a receptor for hyaluronic acid (HA) [47] and can also interact with other ligands, such as osteopontin, collagens and MMPs. CD44 is a fetal and adult hematopoietic stem cell regulator that is involved in cell-cell interactions, cell adhesion and migration and participates in a wide variety of cellular functions, including hematopoiesis and lymphocyte activation, recirculation and homing [48]. CD44 gene contains 20 exons. Ten of these exons (exons l–5 and 16–20) are expressed together on many cell types and the product is referred to as the “standard” form of CD44. Additionally, complex alternative splicing of the transcripts affecting exons from 6 to 15 (variant exons) results in many functionally distinct isoforms or variants (CD44v) [49]. The role of CD44 as a CSC marker has been broadly studied in myeloid leukemia and also in several solid tumors such as lung, brain, liver, head and neck or gastric cancer [50]. In gastric cancer, the first temptative characterization of CSCs in terms of markers was performed by Takaishi and collaborators, who found that CD44+ cells isolated from different gastric cancer cell lines presented sphere formation ability
2.1.4. CD24
CD24 encodes a cell surface sialoglycoprotein that is physiologically expressed in developing or regenerating tissues and regulates processes such as lymphocyte development [59] or neurogenesis [60]. As other stem cell genes, CD24 is expressed in hematologic malignancies and several solid tumors including gastric cancer. Suggesting a role for CD24 in gastric CSCs, some studies by using gastric cancer cell lines have shown that derived spheres are enriched in the expression of CD24 (and CD44) [51] and also that CD24 modulates positively cell migration, while its inhibition entails apoptosis [61]. However, Takaishi et al. were unable to find properties of CSCs in a CD24-positive population in terms of sphere forming capacity and tumorigenicity in mice models [44]. With regard to patients with gastric cancer, CD24 expression progressively increases in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric cancer [61]. Moreover, CD24 expression has been associated with adverse clinicopathological and prognostic aspects such as depth of tumors, lymph node status, TNM stage and reduced overall survival [62], fact that underlines its relevance in the disease.
2.1.5. SOX transcription factors
SOX factors are a family of transcription factors that are emerging as potent regulators of stem cell maintenance and cell fate decisions in multiple organ systems including the gastrointestinal tract [63]. There are at least 20 members divided into eight groups (from A to H), based on their HMG sequence identity in humans. Members within a group preserve higher than 80% identity in their HMG-domain and share other well-conserved regions. In addition, they share biochemical properties, have overlapping expression patterns and perform synergistic or redundant functions [63]. SOX proteins play critical roles during the development of several cell types and tissues in the embryo. They are also essential for stem cell types in the adult through the regulation of the cell fate determination, differentiation and proliferation [63]. SOX members fulfill their role by activating or repressing transcription and their action on target genes is context dependent, relying on other transcription factors with which they may directly interact for specificity. Dysfunction of SOX factors has been implicated in several human diseases. Such diseases are consistent with SOX function and expression pattern during embryonic development. A growing number of evidences are demonstrating that the expression and function of SOX factors are altered in a variety of cancers, and their roles in these malignancies are related to their stemness feature [64].
2.1.5.1. SOX2
SOX2 belongs to the SOXB1 subgroup along with the closely related SOX1 and SOX3. SOX2 is required for establishing embryonic stem cells and the maintenance of the early embryo [65]. It is also one of the factors necessary for reprogramming terminally differentiated cells into induced pluripotent stem cells [66]. Furthermore, SOX2 belongs to the core transcriptionally circuitry found on the regulatory regions of many genes with embryonic stem cell-specific expression [67]. This evidence demonstrates that SOX2 is a key factor in the control of embryonic stem cells fate and activity. SOX2 has additional functions during development, thus emerging as a critical regulator of stem cell maintenance and cell fate decisions. Furthermore, SOX2 also plays a relevant role during adulthood controlling tissue homeostasis and regeneration. Its expression is elevated in different populations of stem cells [68–71], and its high levels can be used to identify quiescent stem cells and distinguish them from transient amplifying progenitors [72, 73]. SOX2 is a regulator of gastric stem cells highly relevant for gastric patterning during development [74] and involved in the physiological renewal of the gastric epithelium in the adulthood [71, 75]. SOX2 displays several roles in cancer as an oncogenic driver, prognostic factor or a marker and regulator of CSCs [76–80]. In GC, its action is controversial. Several authors observed that SOX2 is frequently downregulated in gastric cancer [81–86]. Furthermore, low SOX2 expression is associated with shorter survival time [82] and also with worse prognosis [84]. In contrast, higher SOX2 levels are found among patients who have better prognosis [84]. In a large set of patients, Wang and coworkers demonstrated that SOX2 expression is progressively reduced during gastric carcinogenesis, from normal into invasive cancers including a series of premalignant states, supporting the role of SOX2 decrease as a robust predictor of disease outcome [85]. Similarly, SOX2 downregulation is linked with diffuse type of cancer with SOX2 expression becoming a good biomarker to discriminate between tumor (negative) and non-tumor (positive expression) and also high/low grades of tumor malignancy [86]. The regulation of SOX2 expression in GC has been mostly associated to epigenetic changes. Thus, aberrant DNA methylation has been shown as a key mechanism underlying SOX2 downregulation in a set of primary gastric carcinoma samples [82]. Besides promoter methylation, miR-126 overexpression also decreases SOX2 levels and therefore acts as a tumor suppressor [83]. Recently, it has been shown that SOX2 has an important role in gastric differentiation [87]. It is known that during gastric carcinogenesis, the homeobox transcription factor CDX2 is critical for intestinal differentiation driving the onset of intestinal metaplasia (IM) [88, 89]. Thereafter, Camilo and coworkers showed that SOX2 is associated with gastric differentiation in incomplete IM and is lost in the progression to dysplasia, whereas CDX2 is acquired
2.1.5.2. SOX9
SOX9 is overexpressed in a variety of human cancers, being its high levels correlated with malignant character and progression in prostate, lung, breast and brain tumors [80, 99, 100]. SOX9 expression is also elevated in tumors of the digestive system such as esophageal, colorectal and pancreatic cancers [101, 102]. In esophageal and pancreatic tumors, SOX9 stimulate self-renewal properties [102, 103]. However, in colorectal cancer, there are contradictory results between functional studies and clinical samples, suggesting a context-dependent activity of SOX9 [100, 104]. Remarkably, several studies have reported clinical implications of SOX9 in GC. Thereby, in GC patients, high tumoral SOX9 expression has been observed and associated with advanced TNM stages and lower overall patient survival [105]. Interestingly, in clinical samples, high levels of SOX9 correlate with elevated expression of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) [106], which facilitates GC metastasis, and are positively associated with lymph nodes metastasis and advanced TNM stage [107]. In samples from patients, there is also an inverse relation between SOX9 and the tumor suppressor gastrokine 1 (GKN1), relationship also observed in GC cell lines, wherein GKN1 negatively regulates SOX9 expression [106, 108]. Furthermore, elevated SOX9 expression in gastric tumors is associated with the activation of the WNT canonical oncogenic pathway, with whom it establishes a feedback regulatory loop [105].
Noteworthy, SOX9 is a critical executor of the carcinogenic action of
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