The incidence and mortality of gastric cancer (GC) rank top five and top three, respectively, among cancers around the world. It is an intricate malignancy caused by the reciprocity of intrinsically genetic, environmental, and host-related elements. The silent property, advanced clinical characterization, and potential heterogeneity have made GC a thorny disease with a high death rate. The increasing knowledge of the abundant genetic abnormalities regarding GC will definitely elongate the patients’ survival. Scientists have been working hard to discover the myths beneath gastric tumorigenesis: novel biomarkers have been established, and cell transduction cascades have been well described. The study grouping GC into four molecular subtypes by The Cancer Genome Atlas (TCGA) broadens our horizon of GC etiologies. Knowledge regarding to the sophisticated networks in tumor microenvironment also bring new insights into the mechanisms assist GC development. In the future, people will strive for translating more research achievements into clinical utility. Successful translational medicine will lead to new methods for early GC diagnosis and precise medical strategies for individuals.
- gastric adenocarcinoma
- molecular classification
Gastric cancer (GC) is the fifth most common malignancy worldwide and third leading cancer-related death. Because of poor diagnosis, 5-year survival rate of GC is rather low, ranging from 15 to 52% [1, 2]. The incident rates are higher in men than in women. GC contributes over 20% of morbidity and mortality to cancer all over the world annually, following lung and liver cancer, which account for 23 and 28%, respectively. In 2012, approximate 723,000 deaths and more than 950,000 new GC cases were reported worldwide. Despite the incidence of GC has been declining in the North American and most of the west European countries, GC remains a type of prevailing cancer with increasing risk in regions including Asia, Eastern Europe, and certain areas of Latin America . Particularly, adenocarcinomas, which developed from the glands of the most superficial layer or the mucosa, take up 90% of GC. The rest types of GC include mucosa-associated lymphoid tissue (MALT) lymphomas, which originate from the muscles surrounding mucosa areas of the stomach .
The risk factors include environmental factors, such as
2. The risk factors of GC
GC is defined as a tumor with multifactorial etiologies. Environmental alteration and genetic factors play major roles in GC, particularly, virus infection, dietary habits, and lifestyles are recognized to be critical factors.
Dietary factors: dietary risks, including salty and spicy food intake, cigarettes smoking, frequent coffee, and high-temperature drinking habits are positively associated with GC. Intriguingly, excess salt intake showed susceptibility to EBVaGC and
3. Molecular classification and pathogenies of GC
Up to 90% of stomach malignancies are adenocarcinomas. Non-Hodgkin’s lymphomas and gastrointestinal stromal tumor (GIST) make up most of the remaining 10% . Even though infrequently, adenosquamous, squamous, and undifferentiated carcinomas also occur. In regard to clinical diagnosis, several pathological characterization varied from time to time. Several histological classification systems for gastric adenocarcinoma have been described, but the most frequently used are those of the World Health Organization (WHO) and Lauren . In the World Health Organization (WHO) classification, there are 10 histological types . The Lauren classification is commonly applied and it makes the distinction between intestinal and diffuse types. The intestinal GC consists of cohesive neoplastic cells forming gland-like structures while the diffuse type has lost cell cohesion and resulting in diffuse discohesive cellular infiltration . Men and elderly are more likely to suffer intestinal type, whereas diffuse type carcinomas are relatively more common among the younger population with an equal male-to-female ratio . Recently, a project named The Cancer Genome Atlas (TCGA) has proposed a brand new classification, in which GC is grouped by four subtypes: EBV-positive (EBV), microsatellite instability (MSI), genomically stable , and chromosomal instability [35, 36].
According to previous studies, about 9% of GC cases are infected by EBV . All the EBV-positive GCs harbor the property of CpG island methylator phenotype (CIMP) [36, 38, 39]. EBV-positive tumors exhibited a higher incidence of whole-genomic DNA hypermethylation than any molecular subtypes. The genes with promoter hypermethylation showed most differentially silenced expression in EBV-associated GC . Moreover, PI(3)-kinase inhibition was also strongly detected in EBV-positive GC, which offered a new method for the evaluation of this subtype . The most highly transcribed EBV viral, message RNAs (mRNAs) and microRNAs (miRNAs), fell within the BamH1A region of the viral genome and showed similar expression patterns across tumors . The mutation rate of PIK3CA is exclusively high in EBV-positive gastric cancer compared with other molecular subtypes. The mutation rate of PIK3CA in this subtype is about 80 and 68% of the mutations belongs to recurrent mutation in this dataset. In contrast, in other molecular subtypes, the mutation rates of PIK3CA are from 3 to 42%. So, this result provides a hint that using PI3K inhibitor might have the clinical therapeutic potential for this kind of molecular subtype.
The next subtypes of GC are abundant in MSI, which display increased mutation rates (in major histocompatibility complex class I genes, including B2M and HLA-B) and hypermethylation (containing hypermethylation at the
In genomically stable subtype,
With the somatic copy-number aberrations (SCNAs), the last group of GC was clustered as CIN subtype. In this subtype, a bunch of genes shows dysregulated, such as
4. The dysregulated miRNAs involved in GC
MicroRNAs (miRNAs) are one predominant category of small (roughly 20–30 nucleotides) non-coding RNAs that participate in gene expression and control . Their effects are mostly lead to the degradation of message RNAs (mRNAs) or inhibitory of the translations, and subsequently affect a series of biological behaviors of cells, such as inflammation, cell proliferation, apoptosis and differentiation. In the nucleus, together with its cofactor Pasha (DGCR8), the RNase III enzyme Drosha cut out primary miRNA transcripts into a fragment of approximately 60 nucleotides named precursor miRNAs (pre-miRNAs), and initiate the biogenesis of miRNAs . A cytoplasmic RNase III called Dicer will be responsible for the further processing of the pre-miRNAs and makes them mature after they are transported to the cytoplasm [46, 47]. A mature miRNA, with the length of about 18–24 nucleotides, is single-stranded, which can sometimes aim at multiple targets. These mature miRNAs always bind to the complementary sequences of targeted mRNAs directly to make mRNAs degrade or bind directly to 3′-untranslated regions (3′-UTR) of mRNAs to decrease their translation, so that miRNAs can exert their effects on regulating certain gene expression [44, 48]. Accordingly, miRNAs regulate at least 30% of genes of human as it is estimated .
In other words, miRNAs are capable of acting as a switch to control genes related to cell proliferation and apoptosis under pathogenic circumstances, consequently, they may have a chance to be involved in both cancer initiation and progression. It seems that no matter how clear the mechanism of malignancy behaviors or an effective therapy that might prevent tumorigenesis from the beginning, an increasing knowledge of these miRNAs is crucial. During the physiological periods, miRNAs present or absent in proper time of different stage of lives. However, they are produced abnormally in tumors, that the levels of some miRNAs are highly detected while some are lower or even none. Hence, those which are upregulated called onco-miRs, whereas the downregulated ones called tumor-suppressive miRNAs. As the names suggested, genes controlled by onco-miRs are oncogenes whose products may promote tumor cells in many aspects, whereas the opposite site of genes is tumor suppressive, which plays a role of inhibitor among the initiation or development of tumors (e.g., miR-15a and miR-16-1, which target a member of Hippo pathway called YAP1, are downregulated in GC) . Thus, identifying the target genes of these miRNAs is crucial and it may lead us to a better understanding of the miRNAs themselves.
For example, miR-21 was the first miRNA which was influenced by
5. The tumor microenvironment and gastric carcinogenesis
More and more evidence supported the idea that not only malignant GC cells, but also those nonmalignant cells involved in the tumor microenvironment play indispensable roles throughout GC pathogenesis. Generally, nonmalignant cells participate in various mechanisms related to GC development, such as stromal interactions, angiogenesis, and some immune responses.
Stromal components, including fibroblasts and extracellular matrix (ECM) adjacent to cancer cells, create a suitable environment for GC development. Stromal fibroblasts are known to play a central role in tumor microenvironment by interacting with cancer cells [59, 60]. However, other than ordinary fibroblasts, cancer-associated fibroblasts (CAFs) undergo a phenotypic change into myofibroblasts. Also, CAFs exhibit distinct gene expression patents that pertain to aberrant cell growth, focal adhesion, and ECM remodeling . The remodeling ECM promotes the survival ability and distant colonization cancer cells by synthesizing components, such as type I and type III collagens, fibronectins, tenascin, and versican [62–64], as well as proteases like urokinase, plasminogen activator, fibroblast activation protein (FAP), and matrix metalloproteinases (MMPs) [65–67]. These characteristics are usually associated with poor prognostics. Moreover, tumor-related stromal fibroblasts secrete small molecules, such as IL-6 to stimulate cell growth, as well as factors associated with TGF-β signaling, triggering epithelial-mesenchymal transition (EMT) [68–70].
Angiogenesis is also a pivotal process contributes to tumor progression. Cell population in GC tumor microenvironment regulates the density and architecture of new blood vessels by stimulating the proliferation and differentiation of myofibroblasts and vascular endothelial cells [71, 72]. The growing number of new vessels was reported to facilitate GC metastasis [73, 74]. To promote angiogenesis, GC cells provide numerous angiogenic factors, including VEGF, FGF-2, CXCL1, and Ang-2, to microenvironment [75–78]. It has been noted that high level of VEGF-A contributed to endothelium-dependent angiogenesis. VEGF-A signaling increased both the new blood vessel number and permeability in GC . VEGF-A strongly promotes the angiogenesis and aggressive phenotype of human intestinal-type GC . Bevacizumab is a specific antibody against VEGF-A, and dominantly regulates normal and pathological angiogenesis. Clinical trials of bevacizumab in phase II advanced GC suggested a satisfied curative effect . Unfortunately, in the randomized phase III Avastin in Gastric Cancer (AVAGAST) study, the combination of chemotherapy and bevacizumab did not show a better overall survival extension in the first-line treatment when compared to advanced GC patients, who only subjected chemotherapy . Intriguingly, REGARD and RAINBOW trials using VEGFR2 targeting antibody ramucirumab have also shown a significant increase in the overall survival of patients with advanced GC . It can be partially explained by the geographical differences of GC patients.
Immune reactivity in GC development is based on various types of immune cells in different stages . First, in eliminating stage, macrophages and dendritic cells recruit to secrete chemokines and cytokines, such as IL-12 and IFN-γ, to phagocytize and remove apoptotic cancer cells . Cancer cells survived from elimination subsequently under equilibrium stage and adapted to immune-suppression. The number of tumor-infiltrating lymphocytes (TILs) was noted as independent predictors to evaluate lymph node metastasis and GC patient survival in this stage. Interestingly, TILs exert either oncogenic or tumor-suppressive influence in GC cells, attributing to their unique functions. In a recent report, tumor-associated macrophages with high levels of CD163 expression exhibited aggressive characteristics and expression of cancer stem cell markers in recurrent GC cases. CD163+ macrophages might, therefore, related to independent worse prognosis . T-lymphocyte subsets are also significant cell types associated with both early onset of tumor and tumor progression. It has been reported that the high ratio of CD8+ cytotoxic TILs/FOXP3+ regulatory T cells (Treg) correlated with high overall survival rate and good prognosis, especially in MSI gastric cancer [87, 88]. Eventually, cancer cells escape from immune responses.
Immunogenicity could be blunted by releasing cytokines including TGF-β, TNF-α, and IL-10. Therefore, cancer cells can evade the detection by immune effectors in the tumor microenvironment . PD-1 is one of the most important receptors expressed by T cells and monocytes. PD-1 negatively regulates the effectors by binding to its ligands PD-L1 and PD-L2. Blocking PD-1/PD-L1 has been suggested as a promising immune-therapeutic option [90, 91]. The relationship between PD-L1 level and prognosis remains under debate, however, a recent meta-analysis pooled all present data and suggested PD-L1 to be a valuable prognostic indicator of GC patients by dividing patients into different groups .
Collectively, tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development.
There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years. Epigenetically, we are seeking to unravel the mechanisms of gastric tumorigenesis affected by chromatin remodeling. Besides, there are miRNAs, lncRNAs, and some other classic molecules that are involved in GC development, which requires a more detailed investigation regarding these aspects. The most crucially and urgently, we are struggling to explore specific and precise therapies for patients who are suffering or likely to suffer from GC, especially genomically stable GC (a type of GC with a high mortality).
When it comes to the novel small entities, there are even more issues waiting to be addressed, such as how lncRNAs interact with chromatin alterations during gastric carcinogenesis. Moreover, in addition to
This work is supported by the General Research Fund (RGC Reference No. CUHK14114414 and CUHK14110016) from the Research Grants Council of Hong Kong.
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