Plasticity of Gastric Tumor-Initiating Cells

Global Journal of Pathology & Laboratory Medicine
Volume 1, Issue 2, April 2021, Pages: 58-70
Received: August 20, 2021; Reviewed: September 15, 2021; Accepted: October 05, 2021; Published: October 12, 2021

Unified Citation Journals, Pathology 2021, 1(2) 1-08;
ISSN 2754-0952

Authors: Ms. Andreea Nelson TwakorFile:ORCID iD.svg - Wikimedia Commons

General Medicine Faculty, Ovidius University, Constanta, Romania

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Keywords: Adenocarcinoma, Abnormal Chromatin, Gastric Cancer, Plasticity

1. Abstract:
Gastric cancer is the 5th leading cause of cancer death in the world (7.7% of all cancer deaths) and the 6th most common cancer (11.1% of all cancers) [1]. The human body contains up of two meters of DNA in each cell if stretched end to end. That DNA must be compressed inside the cell nucleus in order to fit [2]. The packing of the genome structure, which is the chromatin, determines how cells respond to stress, according to research in this area. A cell’s plasticity increases when its chromatin packing is disorganized and cannot respond as quickly to outside stimuli when the chromatin is tidy and organized [3].
In this, the investigation is twofold. Firstly, it was investigated the relationship between the degree of plasticity and abnormal chromatin in cancer patients, specifically looking at those with gastric tumors.
It was observed in detail the plasticity of tumor cells and the associations between them and the normal stem cells. Second, stomach metaplasia is linked to tissue atrophy and the loss of the parietal cells that secret acid. This is expected to cause the formation of a metaplastic mucous cell lineage with high amounts of TFF2 (spasmolytic polypeptide), which has been associated to gastric adenocarcinoma [4].
Normal stem cells that get activated in response to unexpected or unfavorable physiological conditions may be the source of cancer stem cells [5]. Thus, the findings of this study suggest that cancer cells are masters of change, the ability given by the relation between abnormal chromatin and tissue exposure to outside conditions.

2. Background:
Gastric cancer results from a combination of environmental factors and the accumulation of specific genetic alterations. The primary prevention includes a healthy diet, anti-H. pylori therapies, chemoprevention, and screening for early detection [7].
More than half of all new cases are seen in underdeveloped nations. Between the greatest and lowest-risk populations, there is a 15–20-fold difference in risk. East Asia (China and Japan), Eastern Europe, Central and South America are also high-risk locations. Southern Asia, North and East Africa, North America, Australia, and New Zealand are low-risk zones [10]

Figure 1 International Agency for Research on Cancer

Figure 1 International Agency for Research on Cancer

Figure 2 Gastric cancer epidemiology

Figure 2 Gastric cancer epidemiology

Figure 3 Gastric cancer risk factors [

Figure 3: Gastric cancer risk factors [9]

3. Research objectives:
This research is looking at different scenarios or cell plasticity as well as molecular mechanisms of gastric carcinogenesis.
Cancer cell plasticity has been considered as a key mechanism that promotes cancer cell diversity and contributes to intra-tumor heterogeneity, along with genetic and epigenetic changes. Cancer cells with plasticity have the ability to go back and forth between a differentiated state with limited tumorigenic potential and an undifferentiated or cancer stem-like state (CSC), which is responsible for long-term tumor growth. It also grants the potential to transition into several CSC states with varying levels of ability to invade, disseminate, and seed metastasis [11]. The epithelial-to-mesenchymal transition program has been related to cancer cell plasticity, which relies not only on cell-autonomous pathways, but also on signals provided by the tumor microenvironment and/or produced in response to therapy. The dynamic transition for cancer cell states, the mechanisms driving cell plasticity, and their impact on tumor development, metastasis, and therapy response are all discussed. Understanding the principles underlying cancer cell adaptability will help researchers develop novel therapeutic approaches [12].

4. Methodology:
For this study, we used literature review as a research method. The research is disparate and interdisciplinary, and it included information from research articles in Pathology, Molecular Biology and Genetics fields.
This research provides a broader look by summarizing and integrating the different guidelines when it comes to plasticity in cancer cells by building on and synthesizing these diverse forms of literature evaluations. The goal of this study is to give an overview of and suggestions for various forms of literature reviews as a research approach in stomach cancer research.

5. Histology and Pathology
Gastric cancer is highly heterogeneous histologically, both architecturally and cytologically, with many histologic features frequently coexisting. Gastric carcinoma is classified clinically as early or advanced stage to help select the best course of treatment, as well as histologically into subtypes based on the predominant morphologic component. When a tumor is found in the proximal stomach or cardia, it might be challenging to classify it based on anatomic location, especially if the tumor also includes the gastroesophageal junction (GEJ) [13]

6. Macroscopy
GCs are classified into three kinds by endoscopists based on their endoscopic appearance. There are three types: protruded (type I), pedunculated (Ip), and sessile (Is); superficial (type II), and excavated (type III). Type II accounts for 80% of EGCs and is further classified into three types: raised (IIa), flat (IIb), and depressed (IIc), with the latter being the most prevalent. Advanced GC can display various gross appearances. Bormann’s classification, which separates GC into four types: polypoid carcinoma (type I), fungating carcinoma (type II), ulcerated carcinoma (type III), and diffusely infiltrative cancer (type IV), is still the most extensively used (type IV) [14].

Figure 4 Growth patterns and macroscopic appearance of advanced gastric cancer according to the Bormann classification [13]

Figure 4 Growth patterns and macroscopic appearance of advanced gastric cancer according to the Bormann classification [13]

6. Macroscopy
According to Lauren’s criteria, gastric cancer is classified into two main types: Intestinal and diffuse type. Intestinal and diffuse gastric cancer exhibit numerous differences in pathology, epidemiology and etiology [15].
Tubular, papillary, mucinous, and poorly cohesive (including signet ring cell carcinoma) are the four major histologic patterns of gastric malignancies recognized by the 2010 WHO classification, as well as unusual histologic variants. The classification is based on the carcinoma’s most prominent histologic pattern, which frequently coexists with less prominent features of other histologic patterns [16].

Figure 5 Representative histological photographs (H&E) of human gastric cancer [17]

Figure 5: Representative histological photographs (H&E) of human gastric cancer [17]

7. Plasticity
Tumor heterogeneity has posed an enduring barrier to the development of cancer medicines in recent decades. This tumor heterogeneity can be inter-tumoral, in which patients with different tumor types have different tumor genotypes, or intra-tumoral, in which cancer cells within the same tumor have different phenotypic and functional heterogeneity. Genetic variety, changes in gene regulation, transitions between cellular states, and environmental disturbances can all contribute to intra-tumor heterogeneity. Cancer progression and treatment failure are fueled by heterogeneity, which makes prognosis difficult and encourages disease recurrence. To explain intra-tumor heterogeneity, two models were presented at first [18].
The first model looks at the clonal evolution model. It entails intrinsic variations between cancer cells induced by stochastic genetic and/or epigenetic changes in individual cells. Over time, cancer cells collect these changes, and better-adapted clones with a growth advantage are chosen. Clonal advantage can vary over time and space. Indeed, extrinsic mechanisms, such as those provided by the different microenvironments within a tumor, confer functional differences upon cancer cells at these different locations [18].
The second model is the cancer stem-like cell (CSC) model. This theory claims that a small group of cells known as cancer stem cells is responsible for tumor formation. CSCs have self-renewing ability, initiate and maintains long-term tumor growth, in contrast to most tumor cells, which have a more differentiated phenotype (non-CSCs) [19].
Lineage-tracing experiments performed in mouse models have demonstrated that adult stem cells with specific mutations are the cells of origin of skin, colon and brain tumors, and that these transformed stem cells act as CSCs. However, some reports have indicated that CSCs could also originate from more committed progenitors by dedifferentiation or reprogramming processes [18].
The third model, recently suggested, refers to the cancer cells that have the dynamic ability to shift between non-CSC and CSC states, as dictated by intrinsic and extrinsic stimuli. Various investigations have supported the idea that CSCs are dynamic populations capable of spontaneous state shifts, and non-stem cells were found to spontaneously switch to stem-like cells in vitro and in vivo [21].
Cell plasticity is the ability of cells to modify their phenotypes in response to environmental signals without undergoing genetic changes. Increased plasticity has been linked to pathological diseases, particularly neoplasms. Barrett’s esophagus, a pre-malignant precursor of esophageal adenocarcinoma, has been cited as an example of plasticity since it involves the transformation of the esophageal squamous lining (multilayer) into an intestinal-like columnar (monolayer) epithelium [22].
Stem cells have also displayed greater plasticity when they are not within their residing tissues, leading to the proposition that the origin of cancer resides in pluripotent stem cells. However, the existence of cancer stem cells (CSCs) may not be the only way that cancer cells acquire their known plasticity. Epigenetic instability followed by genetic instability in the tumor microenvironment may explain such plasticity without resorting to CSCs. [22]

Figure 6 Cancer cell plasticity Impact on tumor progression and therapy response [12]

Figure 6: Cancer cell plasticity: Impact on tumor progression and therapy response [12]

Molecular Mechanisms of Gastric Carcinogenesis
Environmental variables such as H. pylori infection and nutrition, as well as the accumulation of generalized and specific genetic changes, are thought to cause GC. Tahara and Yasui created a model that summarizes the sequence of molecular events for intestinal type and diffuse type GC [23]. The intestinal type of gastric adenocarcinoma is preceded by a sequence of histological lesions (known as Correa´s cascade) with well-defined characteristics: non-atrophic gastritis → multifocal atrophic gastritis without metaplasia → intestinal metaplasia of the complete type → intestinal metaplasia of the incomplete type→ dysplasia [24].
As one can see from this model, there are certain alterations which are common to both major histological subtypes of GC, such as p53 mutation, cyclin E overexpression/amplification, or aberrant CD44 transcripts. Others like KRAS mutations, CDH1 mutations, and amplifications of HER2 FGFR2, and MET appear to be more ‘specific’ for one of the histological subtypes [25].

Figure 7 The Yasui Tahara multistep model of molecular pathogenesis of gastric cancer 25

Figure 7 The Yasui Tahara multistep model of molecular pathogenesis of gastric cancer 25

Figure 8 Summary of cell plasticity models [22]

Figure 8: Summary of cell plasticity models [22]

In various cancers, tumor cells have been shown to hijack developmental processes to adapt to environmental stresses.
Above, there are four scenarios of cell plasticity that represent the current models and challenges. On the chromatin level, epigenetic regulators and DNA elements are shown to be involved in tumor cell tolerance to chemotherapy. On the cellular level, intracellular signaling pathways sensing diverse environmental cues reprogram the transcriptional landscape, leading to adaptation to drug exposures. On the microenvironmental level, inter-cellular communications build up a ‘safe heaven’ by direct cell-to-cell interactions and by ‘quorum sensing’ mechanisms. Psychological distress remotely controls tumor cell adaptation by secreting systemic neurotrophic factors [22].

Chromatin level
Following injury, when it is critical to quickly regenerate and restore tissue integrity and function, other types of cellular plasticity may be crucial for organismal survival. In these contexts, alterations in the epigenetic landscape of tissues are likely to occur in order to allow normally restricted cell fate transitions. Epigenetic mechanisms, particularly DNA methylation and histone modifications, have been shown to play an important role in regulating such plasticity [26].
The reversible feature of the cell plasticity that is triggered upon drug exposure, points towards a key role for transcriptional regulation at both an epigenetic level and a transcription factor. One of the most studied epigenetic regulations in cancer cell plasticity might be histone lysine demethylase 5 (KDM5). KDM5A leads to reduced trimethylation of histone 3 lysine 4 (H3K4me3) and forms a physical interaction complex with histone deacetylase (HDAC) [22].

Cell level: intracellular regulatory pathways
G proteins may be directly or indirectly linked to receptors via most cell surface receptors, which stimulate intracellular target enzymes. These intracellular enzymes act as downstream signalling elements, propagating and amplifying the ligand-binding-induced signal. In most circumstances, intracellular signal transduction involves a series of events that transmit signals from the cell surface to a range of intracellular destinations. Transcription factors, which regulate gene expression, are frequently targets of such signalling cascades. Intracellular signalling pathways connect the cell surface to the nucleus, causing gene expression to change in response to external stimuli [27].

Microenvironmental level: tumor–stroma interactions
Solid tumours are comprised of tumour cells and stromal cells, including fibroblasts, endothelial cells and infiltrated immune cells.
Together with embedded extracellular matrix and vascularisation, the tumour microenvironment is involved not only in tumour growth but also in therapy-induced plasticity. Cancer-associated fibroblasts (CAFs) are among the most well-documented cell populations in promoting therapy resistance.
These cells in turn lead to elevated integrin β1-FAK-Src activation in melanoma cells undergoing treatment, generating a drug-tolerant microenvironment that provides a ‘safe heaven’ for melanoma cells [22].

Systemic Level: Neuronal Factors
Among patients with cancer, emotional distress and psychiatric syndromes are prevalent during the whole period of the treatment, leading to system-level secretion of neuroendocrine hormones and neurotransmitters that could modify the tumor microenvironment and host macroenvironment. Stress sensor TRPA1, a neuronal redox-sensing Ca 2+-influx channel, was shown to mediate Ca 2+-dependent anti-apoptotic pathways and protect cancer cells against chemotherapy, suggesting that cancer cells are capable of tolerating chemotherapy-induced oxidative stress by transmitting a pain signal. This system-level control of tumor adaptive response to anti-cancer treatment has also been reported in targeted therapies [22].

Cancer cells exhibit great plasticity in most tumors, which endows them with the ability to shift dynamically and reversibly between nonCSC and CSC state. Furthermore, CSCs may also transit between states, exhibiting distinct features and abilities to disseminate and give rise to metastatic lesions, which may influence cancer progression and therapy response. In some tumors, this dynamic behavior has been associated with the induction of the EMT program.
Activation of this program results in a reversible switch of phenotypic features, which encompass a spectrum of cells, from epithelial to mesenchymal-like cancer (stem-like) cells, as well as intermediates states, in which cells conserve epithelial features, but also express mesenchymal markers. Cancer cell plasticity depends not only on cancer cell-autonomous mechanisms, such as genetic and epigenetic alterations, but also on signals provided by the tumor microenvironment and/or induced in response to therapy. EMT program is controlled by the complex integration of multiple regulatory networks, which include epigenetic modifications, transcriptional control and activation of specific signaling pathways.
Thus, the expression of EMT-TFs is modulated by DNA methylation, histone modifications, including the establishment of bivalent chromatin that primes gene expression to respond rapidly to stimuli, miRNAs and factors that indirectly regulate these events.
In turn, EMT-TFs inhibit the expression of epithelial genes and induce the expression of mesenchymal state genes by driving the recruitment of DNA methylation and histone modifier enzymes to the promoter of target genes. Furthermore, cytokines and growth factors provided by CAFs, mesenchymal stem cells, endothelial cells and determined immune cells, as well as hypoxia, can trigger transcriptional and epigenetic programs, leading to the acquisition of plasticity, induction of stemness and (partial) EMT.
In addition, cancer cells may remodel their niche to promote proliferation, stemness and EMT, angiogenesis and escape from immune surveillance.
Therefore, integration of all these mechanisms operating at different levels may give rise to intermediate states or hybrid epithelial/mesenchymal cells, which show a strong capacity to adapt rapidly to different stresses during tumor growth or in response to therapy. This extraordinary capability to adapt to microenvironmental changes is an important challenge to therapeutic interventions. Therefore, further studies are needed to provide insight into the mechanisms that regulate cancer cell plasticity, in order to design new therapeutic interventions targeted to block EMT/stemness or to eradicate mesenchymal or hybrid cancer cells, acting on cancer cells or the tumor microenvironment.


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To citation of this article: Ms. Andreea Nelson Twakor, Plasticity of Gastric Tumor-Initiating Cells, Global Journal of Pathology & Laboratory Medicine

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