Gastric Adenocarcinoma: The Use of Animal Models to Research Risk Factors, Prevention, and Treatment Approaches

The disease known as gastric cancer occurs when the stomach lining develops malignant (cancer) cells.  The epidemiology of gastric cancer has evolved in recent decades, making it the second most common cause of cancer-related deaths worldwide ^[1]. It is often believed that Helicobacter pylori infection causes gastric cancer (GC) by starting a process known as Correa's cascade, which moves from chronic non-atrophic gastritis to atrophic gastritis, intestinal metaplasia, and finally dysplasia. In stomach cancer treatment, surgical resection augmented with standardized lymphadenectomy continues to be the gold standard ^[2].  Any tumor of the stomach is referred to as a gastric tumor.   Both benign and malignant (gastric cancer) forms are possible.  Columnar epithelium organized with pits called crypts makes up the stomach mucosa. When malignant (cancer) cells develop in the stomach lining, it is known as gastric cancer.  The epidemiology of GC, the second most common cause of cancer-related deaths worldwide, has evolved in recent decades. It is often believed that Helicobacter pylori infection causes gastric cancer by starting a process known as Correa's cascade, which moves from chronic non-atrophic gastritis to atrophic gastritis, intestinal metaplasia, and finally dysplasia. The gold standard for treating gastric cancer is still surgical resection augmented with standardized lymphadenectomy ^[4]. A stomach tumor is known as a gastric tumor. It may be malignant or benign.  The columnar epithelium that makes up the stomach mucosa is structured in pits called crypts. Ninety percent of the many cell types that constitute the gastric mucosa and give rise to gastric tumors are adenocarcinomas.  Most often found at a late stage, gastric tumors are metastatic ^[3].

Sporadic gastric cancer (SGC)

Most cases of GC are intermittent and primarily impact individuals over 45. We call these carcinomas SGCs.  Numerous environmental elements often converge to cause them.  Males are two times more likely than females to be impacted, especially in high-risk nations, and they often occur between the ages of 60 and 80.

Early onset gastric cancer (EOGC)

GCs under 45 are referred to as EOGCs, which includes roughly 10% of GCs above 45. Genetic factors appear to be the cause of EOGCs ^[4].  These tumors are more common in women, most likely due to hormonal reasons, and are typically multifocal and diffuse ^[6]. At the molecular level, SGC and EOGC differ as well. However, other from these dietary GC cases, the pathophysiology of EOGC is still unknown ^[4].

Gastric stump cancer (GSC)

GSC, a distinct subtype of GC, is characterized by gastric residual carcinoma that develops at least five years following peptic ulcer surgery ^[7]. Males are more likely than females to develop GSC, which accounts for 1.1% to 7% of all GCs ^{[5, 6].}

Exploration of Gastric Cancer in Animal Models

Rat Model

Many researchers began attempting to artificially cause stomach tumors in animals in the 1930s with a variety of carcinogens, including 2-acethylaminofluorene, 3-methylcholanthrene, and benzo[a]pyrene. It was only in 1967 that Sugimura and Fujimura were able to report good yields of adenocarcinomas in the glandular stomachs of rats treated with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Nevertheless, the occurrences of experimentally caused stomach cancer were modest. There are erosive lesions, disordering of glandular structures, and growth of pyloric mucosa in the rat glandular stomach exposed to MNNG. Atypical glands and stomach cancer cells can then be seen, and in the end, this model induces both differentiated and undifferentiated stomach carcinomas that resemble the histological kinds of stomach cancer found in humans.  Animals' stomachs are more susceptible to the effects of carcinogens when surfactants, like alkyl benzenesulfonate, are present ^{[6, 7]}.

Mouse Model

In general, it has been discovered that mice's glandular stomachs are comparatively resistant to MNNG activity. Over the course of their lives, BRSUNT/NJms mice given MNNG in their drinking water only developed adenomatous hyperplasia of the stomach epithelium.  However, the stomach and several other organs did develop carcinomas when 4-nitroquinoline 1-oxide (4-NQO) and 4-hydroxyaminoquinoline 1-oxide (4-HAQO) were administered orally. Then, it was observed that BALB/c and C3H mice treated with N-methyl-N-nitrosourea (MNU) developed good yields of adenocarcinomas in their glandular stomachs.  The development of mouse models made it possible to use transgenic and knockout animals in novel ways. The anatomy of the stomach differs in mice and humans. In mice, squamous rather than oxyntic glandular epithelium lines the homologue of the gastric fundus. As a result, unlike in normal human anatomy, the squamocolumnar junction in mice does not always resemble the gastroesophageal junction.  Furthermore, although spontaneous stomach adenocarcinomas have been reported in cotton rats (Sigmodonhispidus) and the Z strain of the African rodent Mastomysnatalensis, rodents hardly ever develop spontaneous gastric cancer. However, enterochromaffin-like cell carcinoids are more commonly seen in these animals when they form stomach cancers.  As a result, research has concentrated on finding chemical, viral, or genetic ways to cause stomach cancer in animals^{[8, 9]}.

Dog Model

The administration of MNNG to dogs through their drinking water was also found to cause a high rate of glandular stomach tumors. These animals allowed for the successive collection of stomach samples and endoscopic monitoring.  Dogs fed N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG) can also develop stomach tumors, albeit the yields are less than those of MNNG ^[10].

Mongolian Gerbil Model

One of the main causes of stomach problems is Helicobacter pylori (H. pylori), and there is substantial epidemiological evidence linking it to the development of cancer as well as active chronic gastritis, peptic ulcers, atrophic gastritis, intestinal metaplasia (IM), and malignant lymphoma.  In 1994, WHO/IARC classified H. pylori as a "definite biological carcinogen" based on epidemiological data ^{[9, 11]}. In order to research the pathogenetic backdrop, many animals have been successfully infected with human H. pylori. However, none of the early models that were examined proved to be sufficiently similar to the circumstances surrounding human H. pylori infection and pathology.  However, a Mongolian gerbil (MG) model of human H. pylori infection was reported by Hirayama et al. in 1996. The germs were detectable for a 12-month study period.  The resulting IM, peptic ulcers, and chronic active gastritis resemble human lesions.  Then, in 1998, it was reported that MGs with MNU and MNNG as carcinogens had been used to create an animal model of stomach carcinogenesis.  Additionally, it was discovered that H. pylori infection raised the incidence of adenocarcinomas of all histological categories in the MG glandular stomach, both MNU- and MNNG-induced.  For the study of stomach carcinogenesis, this model has proven to be highly helpful ^{[11, 12, 13]}.

Overview of spontaneous tumor models in rats and mice

It can be difficult to work with spontaneous tumor models since tumor formation varies from animal to animal and may only occur in older animals.   Genetically engineered models (GEMs) for cancer provide the advantage of having tumors grow de novo in the right tissue under the right conditions.  In a syngeneic tumor experiment, tumors from the cancer GEM (with or without additional in vitro expansion) are implanted into wild type mice of the same background strain, making it easier to create a concurrent research cohort ^{[14, 15]}.

Tumor models caused by viruses

Important insights into cell biology and cell transformation have been gained from the study of virus–cell interactions.  The study of cancer-related viruses and the model systems used to investigate these mechanisms have substantially advanced our knowledge of diseases linked to bio medically significant viruses and created fundamental paradigms for virus–cell interactions.   In recent times, some viruses known as oncolytic viruses have been employed as cancer-fighting agents. The ILAR Journal devoted an entire issue to models of virus-induced carcinogenesis and oncolytic viruses because of this background models of radiation-induced tumors ^[16,17]. Although there are many different possible ionizing radiation exposure scenarios, each one carries risks that go beyond the basic concerns of immediate survival.   Radiation exposure bears the consequence of increased cancer risk, whether it is intentional exposure to fractionated doses as part of a treatment plan or unintentional exposure to a single, whole-body dosage during a terrorist act.   Treatments designed particularly to minimize the mutations and precancerous replication that occurs after irradiation may be able to lessen the long-term effects of both purposeful and incidental exposure. A significant amount of in vitro testing would surely be required for the development of such medicines, but well-understood animal models are required to correctly replicate the intricate process of radiation-induced carcinogenesis.  Because of their many molecular and physiological parallels to humans, inbred strains of the laboratory mouse, Mus musculus, make the most sense.   Their usefulness for use in cancer research is further increased by their small size, high breeding rate, and fully sequenced genome ^{[14, 17]}.

Chemically induced tumor models

The ability to identify carcinogens from the environment, food, and workplace has made chemical carcinogenesis studies in animals a direct factor in lowering the cancer load in the human population.  The incidence of cancer has decreased in exposed populations as a result of decreased exposure to certain carcinogens through changes in industrial practices, government regulations, or lifestyle choices. Furthermore, animal models of environmentally generated cancer have and will continue to offer valuable insights into the origins, mechanisms, and conceptual frameworks of cancer. These models also provided the first experimental evidence for the association between chemical and radiation exposure and cancer. Genetically altered mouse models (GEMMs) combined with chemical carcinogens have become a helpful tool for studying the intricate relationship between environment and genotype that leads to the development of cancer.  Future research on topics like the epigenetic foundation of cancer, genetic modifiers of cancer susceptibility, the systems biology of cancer, inflammation and cancer, and cancer prevention is probably going to be aided by animal models of environmentally generated cancer^{[12, 18]}.

Transplantable tumor models

There have never been any mouse stomach cancer cell lines that could be transplanted into C57BL/6 mice before.  However, evaluating potential treatments would benefit from using an immunocompetent mouse model of stomach cancer.  C57BL/6 mice and p53 heterozygous knockout mice were fed N-Methyl-N-nitrosourea (MNU) in their drinking water.  It was possible to cultivate and s.c. transplant cells from a single tumor from a p53 knockout animal into a C57BL/6 mice.  We subcloned this s.c. tumor after cultivating it. Microarray analysis was used to compare the mRNA expression of the most aggressive YTN16 subline to that of the less aggressive YTN2 subline. Additionally, fibroblast growth factor receptor 4 (FGFR4) in YTN16 cells was suppressed by a FGFR4 specific inhibitor, BLU9931, and knocked out using a CRISPR/Cas9 system. In C57BL/6 mice, these transplanted cell lines developed s.c. tumors.  Four cell lines were generated and subcloned: YTN2, YTN3, YTN5, and YTN16.  They grew at comparable rates in vitro. However, compared to YTN5 and YTN16, YTN2 and YTN3 had decreased rates of peritoneal dissemination, metastatic growth, ands.c. tumor development ^{[19, 20, 21]}.

Risk factors:

Gender: Men are more likely than women to have stomach cancer. Age: Although stomach cancer can strike anyone at any age, the risk increases with age. The majority of stomach cancer patients are in their 60s, 70s, or 80s.

Helicobacter pylori infection

One of the main causes of stomach cancer, particularly those that affect the lower (distal) portion of the stomach, appears to be Helicobacter pylori (H pylori) infection.  Atrophic gastritis and other precancerous alterations of the stomach's inner lining might result after a prolonged infection of the stomach with this bacterium. H pylori infections are more common in patients with stomach cancer than in those without the disease.  A H pylori infection is also connected to certain stomach lymphoma forms.  Even Nevertheless, the majority of people who have this stomach germ never get cancer ^{[15, 22]}.

Being overweight or obese

Obesity and excess weight are associated with a higher risk of cardia (the top portion of the stomach near the esophagus) malignancies.

Diet

People who eat a lot of salt-preserved foods, like pickled vegetables and salted meat and fish, are more likely to get stomach cancer.  Regular consumption of processed, grilled, or charcoaled meats seems to raise the risk of stomach tumors that are not cardiac.  The risk of stomach cancer is probably increased by eating little or no fruits.  However, eating a lot of raw vegetables and fresh fruits, particularly citrus fruits, seems to reduce the incidence of stomach cancer.  Regular consumption of processed, grilled, or charcoaled meats seems to raise the risk of stomach tumors that are not cardiac. The risk of stomach cancer is probably increased by eating little or no fruits.   However, eating a lot of raw vegetables and fresh fruits, particularly citrus fruits, seems to reduce the incidence of stomach cancer.   Since nitrate is converted to nitrite and then reacts with other nitrogen-containing substances to form N-nitroso compounds, foods high in nitrate may play a role. Animal studies have shown that N-nitroso compounds, such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), are carcinogenic and mutagenic according to Druckrey, 1975; Magee et al, 1976; Bulay et al, 1979.

Environmental and behavioural factors

Numerous behavioral and environmental factors influence the development of stomach cancer. Nowadays, smoking is seen as a major contributing factor.  According to a 1997 meta-analysis, present and former smokers have a 44% higher risk of developing stomach cancer.  According to a second, more thorough meta-analysis conducted in 2007, this risk increase was 20% for women and 60% for men.   Smoking exposure at any point in the patient's life was associated with a population-attributable risk of 18% and 45% for the development of cardia and non-cardia gastric carcinomas, respectively, in a population-based case control research ^[17].

Alcohol use

Alcohol consumption most likely raises the risk of stomach cancer. The best evidence for this connection is found in those who consume three or more drinks daily.

Tobacco use

Smoking raises the risk of stomach cancer, especially those that affect the top portion of the stomach close to the esophagus. Smokers are approximately twice as likely to develop stomach cancer. Smoking raises the risk of stomach cancer, especially for tumors that affect the section of the stomach that is closest to the esophagus. Smokers have a roughly twofold increased risk of stomach cancer ^{[23, 24]}.

Ethnic and geographic factors

The incidence of stomach cancer is higher in non-Caucasian groups. Native American (21.6/100,000) and Asian (20/100,000) populations in the US have the highest incidence. Racial and sex differences impact the likelihood of developing an illness and the ensuing death rate. Male African-Americans have the greatest death rate due to ethnicity and sex (12.4/100,000) ^[25]. The overall 5-year survival rates for the various races are comparable, nevertheless.  Geographically, there are also significant differences in the incidence of stomach cancer.  As the most frequent tumor type in Japan, where it accounts for about 19% of new tumor diagnoses based on 2001 cancer registry data, the societal burden of stomach cancer is significantly higher than that of the American population.  The incidence rate among Japanese men is 116/100,000 ^{[26, 27]}.

Genetics factor

Numerous genes raise the risk of stomach cancer, and they are described in A significant proportion of stomach tumors have been shown to have particular genes, including p53 tumor suppressor genes, APC, and MCC.  E-cadherin, a calcium-dependent adhesion protein that binds cells to one another, has been found in numerous studies to play a significant role in the cascade of gastric carcinogenesis.  A single mutant CDH1 allele is transmitted hereditarily in cases of genetic vulnerability. Increased intracellular permeability results from a loss of intracellular adhesion caused by an acquired mutation of the second allele in the E-cadherin gene. Families of gastric cancer have been found to have a wide range of mutations in this area. Gastric carcinoma is linked to a number of syndromes, the majority of which are linked to the development of gastrointestinal polyps and also carry an elevated risk of cancer in other locations. These include Cowden disease and familial adenomatous polyposis (FAP). The APC gene, which is implicated in the tumor-signaling pathway, contains the FAP genetic abnormality. This gene, which is found on chromosome 5q, is involved in the formation of several tumor types, such as stomach and colon cancers ^[15].

Obesity

Cancers of the cardia, the portion of the stomach closest to the esophagus, have been linked to being extremely overweight or obese, however the degree of this association is still unclear ^[28].

Previous stomach surgery

In patients who have had a portion of their stomach removed to treat non-cancerous conditions like ulcers, stomach malignancies are more likely to develop.  This could be because the stomach produces less acid, which provides room for more dangerous bacteria. Another factor that could raise the risk is bile reflux, or backup, from the small intestine into the stomach following surgery.  Usually, years pass after the procedure before these cancers appear ^[8].

Inherited cancer syndromes

Some persons have disorders that can increase their risk of stomach cancer due to gene mutations (changes) that they acquire from their parents. Less than 1% of stomach cancers globally are caused by these hereditary disorders.

Family history of stomach cancer

Even those without one of the inherited cancer syndromes mentioned above are at a higher risk of developing stomach cancer if they have first-degree relatives (parents, siblings, or children) who have had the disease.  However, the majority of stomach cancer patients do not have a family history of the disease ^[26].

Common variable immune deficiency (CVID)

The immune system of patients with CVID is unable to produce enough antibodies to aid in defense against infections.  In addition to other issues including atrophic gastritis and pernicious anemia, this might result in recurrent infections.  The risk of stomach cancer and gastric lymphoma is higher in people with CVID ^[28].

Having type, A blood group

Red blood cells and several other cell types typically have specific chemicals on their surface that are referred to as blood type groups.  When it comes to transplant blood matching, these groupings are crucial. People with type A blood have an increased risk of stomach cancer for unclear causes.

Prevention:

Diet, Nutrition

Dietary variables play a significant role in the development of stomach cancer, particularly intestinal adenocarcinoma. A lower risk of stomach cancer may be linked to healthy eating practices, such as eating a lot of fresh produce, a Mediterranean diet, a low-sodium diet, salt-preserved foods, red and highly cured meat, consuming alcohol in moderation, and keeping a healthy weight ^{[25, 29]}.

Not smoking

Smoking raises the chance of upper stomach cancer, which is the part closest to the esophagus.  Do not use tobacco, and do not begin using it, as it raises the risk for numerous other forms of cancer.

Treating H pylori infection

The use of antibiotics to treat individuals with a persistent H pylori bacterial infection of the stomach linings who do not exhibit any symptoms is still unclear.  Current study is being done on this subject.  According to certain research, treating patients with a H pylori infection with antibiotics may reduce the amount of precancerous stomach lesions and the chance of stomach cancer. However, not every study has discovered this ^{[7, 10]}. Some study has indicated that treating H pylori patients who are also at a higher risk for stomach cancer due to other factors, such as having a close relative with stomach cancer, may be beneficial, even though it is still unclear if all patients with H pylori infection should receive treatment ^{[6, 7]}.

Aspirin use

Stomach cancer appears to be reduced by using aspirin or other non-steroidal anti-inflammatory medicines (NSAIDs), such as naproxen or ibuprofen.  Additionally, these medications can reduce the incidence of colon cancer and colon polyps.  However, in certain persons, they can also result in severe (and even fatal) internal bleeding as well as other possible health hazards ^{[2, 4]}.

Clinical Trials:

Clinical trials are investigations that assess a novel medical strategy, tool, medication, or other therapy. Open trials are research projects that are currently taking new participants. Closed trials may open in the future, but they are not presently accepting enrolment ^[30].

Treatment:

There are different types of treatment for patients with gastric cancer.

• Seven types of standard treatment are used:
• Surgery
• Endoscopic mucosal resection
• Chemotherapy
• Radiation therapy
• Chemoradiation
• Targeted therapy
• Immunotherapy

All stages of stomach cancer are frequently treated with surgery.  The following surgical techniques may be applied. A subtotal gastrectomy involves removing the cancerous portion of the stomach together with any surrounding lymph nodes and portions of other organs and tissues.  It is possible to remove the spleen. The spleen produces lymphocytes, stores lymphocytes and red blood cells, filters blood, and eliminates old blood cells.  On the left side of the abdomen, close to the stomach, is the spleen ^{[4, 6, 10]}. The entire stomach, any surrounding lymph nodes, and portions of the small intestine, esophagus, and other tissues close to the tumor are removed during a total gastrectomy. It is possible to remove the spleen.  To enable the patient to continue eating and swallowing, the esophagus is joined to the small intestine. The following methods may be utilized if the tumor is obstructing the stomach but regular surgery is unable to remove the cancer entirely ^{[8, 25]}. The process of inserting a stent—a thin, inflatable tube—to maintain an open passageway, like the esophagus or arteries, is known as endoluminal stent implantation.  To enable the patient to eat regularly, surgery may be performed to implant a stent from the esophagus to the stomach or from the stomach to the small intestine in cases where tumors are obstructing the route into or out of the stomach. Endoluminal laser therapy involves inserting a laser-equipped endoscope—a thin, illuminated tube—into the patient's body.   A laser is a powerful light beam with knife-like capabilities. Surgery known as gastrojejunostomy is used to remove the cancerous portion of the stomach that is obstructing the small intestine's entrance.  Food and medication can go from the stomach into the small intestine thanks to the connection between the stomach and the jejunum, a section of the small intestine ^{[7, 21]}. Endoscopic mucosal excision is a non-surgical technique that removes precancerous growths and early-stage malignancy from the lining of the digestive tract using an endoscope. A narrow, tube-shaped device containing a light and a viewing lens is called an endoscope. It might also contain instruments for excising growths from the intestinal lining. Chemotherapy is a type of cancer treatment that involves the use of medications to either kill or prevent the division of cancer cells.  Chemotherapy medications can enter the bloodstream and reach cancer cells all throughout the body when they are either orally or administered intravenously or intramuscularly (systemic chemotherapy).  Chemotherapy mostly targets cancer cells in the places where it is administered, such as the abdomen, when it is injected directly into the cerebrospinal fluid, an organ, or a bodily cavity.  The kind and stage of the cancer being treated determine how the chemotherapy is administered ^{[23, 29]}. Intraperitoneal (IP) chemotherapy is one kind of regional chemotherapy being researched for the treatment of gastric cancer.  Through a tiny catheter, the anticancer medications are delivered straight into the peritoneal cavity, which houses the abdominal organs, during IP chemotherapy. One surgical treatment for gastric cancer under investigation is hyperthermic intraperitoneal chemotherapy.  Chemotherapy is administered directly into the peritoneal cavity once the surgeon has removed as much tumor tissue as possible ^{[18, 26].}Cyramza (Ramucirumab), Docetaxel Doxorubicin Hydrochloride, Enhertu (Fam-TrastuzumabDeruxtecan-nxki), 5-FU (Fluorouracil Injection), Fam-TrastuzumabDeruxtecan-nxki, Fluorouracil Injection, Herceptin (Trastuzumab), Keytruda (Pembrolizumab), Lonsurf (Trifluridine and Tipiracil Hydrochloride), Mitomycin, Nivolumab, Opdivo (Nivolumab), Pembrolizumab, Ramucirumab, Taxotere (Docetaxel), Trastuzumab, Trifluridine, and Tipiracil Hydrochloride are among the medications approved for Stomach (Gastric) Cancer. Cysplatin plus either 5-FU or capecitabine, Oxaliplatin plus 5-FU/leucovorin (FOLFOX), Oxaliplatin plus capecitabine (CAPOX), and Irinotecan plus 5-FU/leucovorin (FOLFIRI) are drug combinations used to treat stomach (gastric) cancer. High energy x-rays or other forms of radiation are used in radiation therapy, a cancer treatment, to either kill or stop the growth of cancer cells.  External radiation therapy directs radiation toward the cancerous part of the body using an equipment outside the body ^[4]. Chemoradiation treatment enhances the effects of radiation therapy and chemotherapy by combining the two. Adjuvant therapy is chemotherapy used after surgery to reduce the chance of cancer recurrence.  Research is being done on neoadjuvant therapy, which is chemotherapy and radiation administered prior to surgery to reduce the tumor ^{[18, 26]}. Drugs or other chemicals are used in targeted therapy to locate and target particular cancer cells. Targeted treatments typically injure normal cells less than radiation or chemotherapy. Multichines inhibitors and monoclonal antibodies are two examples of targeted therapies used to treat gastric cancer. [13.14%] Laboratory-made immune system proteins called monoclonal antibodies are used to treat a variety of illnesses, including cancer.  In order to treat cancer, these antibodies can bind to a particular target on cancer cells or other cells that might support the growth of cancer cells.  After that, the antibodies have the power to either eradicate the cancer cells or prevent them from proliferating. Monoclonal antibodies are administered intravenously. They can be employed alone or to deliver radioactive substances, poisons, or medications straight to cancer cells.  Monoclonal antibody medications come in a variety of forms. The growth factor protein HER2 transmits growth signals to gastric cancer cells, however trastuzumab prevents this from happening. Vascular endothelial growth factor is one of the proteins whose effects are blocked by ramucirumab. This could kill cancer cells and prevent them from proliferating.  Additionally, it might stop the development of new blood vessels, which cancers require in order to proliferate.  Stage IV gastric cancer and gastric cancer that cannot be surgically excised or that has returned are treated with trastuzumab and ramucirumab ^[26]. immunological checkpoint inhibitor therapy: T cells' surface protein PD-1 aids in regulating the body's immunological responses.  Certain cancer cell types have a protein called PD-L1. PD-1 prevents the T cell from destroying the cancer cell when it binds to PD-L1.   Inhibitors of PD-1 and PD-L1 prevent the proteins from binding to one another.  The T cells are able to eliminate cancer cells as a result.  A particular kind of PD-1 inhibitor is pembrolizumab ^[18]. Immunotherapy fights cancer by utilizing the patient's immune system. The body's natural defenses against cancer are strengthened, guided, or restored by substances produced in the lab or by the body itself.  Biologic therapy is the term used to describe this cancer treatment. One kind of immunotherapy is immune checkpoint inhibitor therapy.

Supportive care: palliative care

Improving quality of life—rather than necessarily length—is the main objective of palliative therapy for people with stomach cancer. Resection, bypass, stenting, and chemotherapy are the four primary palliative care techniques for advanced stomach cancer that are covered. ^{[22, 31]}. Palliative care for cancer has been defined by the World Health Organization (WHO) as By preventing and alleviating suffering through early detection, accurate assessment, and treatment of pain and other physical, psychological, and spiritual issues, palliative care helps patients and their families deal with their condition. Numerous studies show that palliative care helps people with advanced cancer manage their symptoms and enhance their quality of life ^[4,5,6]. Palliative care ought to be provided early on as well as near the end of life. Scarpi et al. demonstrated that patients with GAC have a higher quality of life when systematic palliative care is implemented early ^[8]. Palliative care, when provided, decreased the need for more intense treatment as patients neared the end of their lives, according to Merchant et al. ^[9]. Sometimes patients' health can be sufficiently improved by early symptom management that they are even able to withstand anti-cancer treatment ^{[30, 31]}. Early satiety, nausea, vomiting, anemia, discomfort, and weight loss are typical early signs of GAC. Chronic or ongoing bleeding from GAC results in anemia. Fatigue, discomfort, and appetite loss were the most common complaints among patients receiving treatment in the second line setting, according to a review of those individuals ^{[8, 9]}. Furthermore, research demonstrated that the quality of life, particularly emotional functioning, pain, appetite loss, nausea, and vomiting, improved when comprehensive therapy was in place ^[9]. Systemic therapy has the potential to improve Eastern Cooperative Oncology Group (ECOG) performance status (PS) even after third line therapy ^[11]. Severe bleeding or malignant gastric outlet obstruction (GOO) can result from large primary GAC. Multidisciplinary techniques such endoscopy, surgery, and/or radiotherapy are required to treat GOO or hemorrhag ^{[14, 24]}. Palliative gastrectomy: Palliative resection is necessary when symptoms of advanced GAC, such as bleeding, blockage, or perforation, occur. Although endoscopic procedures and arterial embolization are recommended for reducing bleeding, in certain cases, gastrectomy becomes necessary.  Gastrectomy is a better option than bypass surgery for treating blockage.   Gastrectomy is required for perforation; nevertheless, postoperative morbidity is substantial. ^{[19, 20]}. There is disagreement in some quarters over whether palliative gastrectomy can improve the prognosis of individuals with Stage IV GAC. Patients who underwent palliative gastrectomy tended to have a higher survival rate than those who did not, according to a number of retrospective studies. In contrast, the REGATTA research, a phase 3 randomized controlled trial, demonstrated that patients with Stage IV GAC did not benefit from palliative gastrectomy before to chemotherapy in terms of survival.  It is significant to note that patients who had a total gastrectomy had a worse tolerance for chemotherapy. The choice to do a palliative gastrectomy ought to be carefully considered and discussed with other medical professionals ^{[25, 22]}.

Bypass:

Due to distal GAC, gastrojejunostomy (GJ) works well for GOO. 88% of patients who underwent stomach-partitioning GJ, a form of bypass technique, were able to resume their regular eating habits two weeks following the procedure.   GJ has been thought to be better than SEMS in a number of ways.  According to one report, patients who had GJ were able to eat regularly at two weeks, whereas those who had SEMS were unable to do so; 12 out of 16 patients in the GJ group were eating by mouth, while just 1 out of 9 patients in the SEMS group were doing so.   Second, compared to SEMS, GJ's risk of re-intervention was considerably lower. Third, a number of studies demonstrated that GJ was substantially linked to a longer overall survival. However, the drawbacks are increased postoperative morbidity and lengthier hospital stays. GJ is therefore appropriate for patients with strong performance status and a high chance of long-term survival ^{[26, 27, 30, 31]}. Lately, less invasive techniques like EUS-GJ and Lap-GJ have been employed. Lap-GJ was linked to lower intraoperative blood loss, postoperative delayed stomach emptying, and postoperative hospital stays, according to earlier research comparing it to open-GJ. Compared to Lap-GJ, EUS-GJ was less intrusive.  In EUS-GJ, a lumen-apposing, totally covered, self-expanding metal stent is inserted through a fistulous passage created by EUS between the stomach and the jejunum. Compared to Lap-GJ, EUS-GJ was demonstrated to be less morbid and practicable.  Compared to laparoscopic GJ, EUS-GJ is less expensive. For patients who might not be able to handle surgery, EUS-GJ appears to be the best option ^{[27, 30]}. A bypass operation for obstruction brought on by cancer of the esophagogastric junction need to be regarded as quite invasive. Baba et al. proposed oesophageal bypass surgery for oesophageal cancer, which involves retrogradely inserting a decompression tube after a Y-shaped stomach tube. Only a small percentage of individuals with esophagogastric junction cancer, whose tumor is contained to the esophagogastric junction and does not spread to the stomach, appear to benefit from it ^{[11, 13, 15]}. One method for managing localized symptoms such pain, bleeding, and blockage is palliative radiation therapy. Compared to other therapies, radiotherapy is less intrusive.  Surgery, endoscopic procedures, or interventional radiology treatments are appropriate in an emergency because radiation response can be delayed.  30 Gy in 10 parts was the most widely used dose.  Whether raising the RT dose is more beneficial or not is still up for debate ^[13].  This review could have clarified Even while stomach cancer has been less common over the last few decades, it is still a significant public health issue. One of the main causes of stomach problems in humans, including neoplasia, is Helicobacter pylori (H. Pylori). Additionally, there are sporadic subtypes of gastric cancer that are closely linked to environmental risk factors.  Certain pathways of stomach cancer genesis have been clarified, leading to primary and secondary preventative measures include eliminating H. pylori and leading a healthy lifestyle.

CONCLUSION:

This study emphasizes how crucial early detection and prevention techniques are to the treatment of stomach cancer. Tumor stage, patient performance, therapeutic objectives, and technological viability should all be taken into consideration while choosing a treatment. Early-stage stomach cancer can frequently be effectively treated with chemotherapy and supportive medicines without invasive surgery, however surgery plus chemotherapy and radiation therapy is still the most effective treatment in advanced stages. In order to comprehend disease mechanisms and assess new therapeutic medicines, animal models—such as spontaneous and induced tumor models in rats and mice—remain essential. Additionally, the diagnosis of minor and early stomach lesions has been increased due to developments in endoscopic procedures such dye spraying and zoom endoscopy, which boost the odds of prompt intervention. In order to improve clinical outcomes and support individualized treatment plans, future research should concentrate on genetic investigations, novel drug development, and cutting-edge diagnostic techniques. The most promising approach to lessening the incidence of stomach cancer and raising patient survival rates is to combine diet, lifestyle changes, early detection, and cutting-edge treatments.

REFERENCES

1. Cao X, Tsukamoto T, Nozaki K, Mizoshita T, Ogasawara N, Tanaka H, et al. Gastric adenocarcinoma: screening of animal model study of risk factor, prevention and treatment. 2004.
2. Skierucha M, Milne AN, Offer Haus GJ, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol. 2016;22(8):2460-74.
3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Gastric adenocarcinoma: screening of animal model study of risk factor, prevention and treatment scenario. 2008.
4. Kikuchi S, Nakajima T, Nishi T, et al. Association between family history and gastric carcinoma among young adults. Jpn J Cancer Res. 1996;87(4):332-6.
5. Thorban S, Böttcher K, Etter M, Roder JD, Busch R, Siewert JR. Prognostic factors in gastric stump carcinoma. Ann Surg. 2000;231(2):188-94.
6. Correa P, Piazuelo MB. Helicobacter pylori infection and gastric adenocarcinoma. US GastroenterolHepatol Rev. 2011;7(1):59.
7. Ajani JA, Lee J, Sano T, Janjigian YY, Fan D, Song S. Gastric adenocarcinoma. Nat Rev Dis Primers. 2017;3(1):1-19.
8. Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparoscopy in the management of gastric adenocarcinoma. Ann Surg. 1997;225(3):262-7.
9. Shibata D, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992;140(4):769-74.
10. Werner M, Becker KF, Keller G, Höfler H. Gastric adenocarcinoma: pathomorphology and molecular pathology. J Cancer Res Clinical. 2001;127(4):207-16.
11. Tan P, Yeoh KG. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology. 2015;149(5):1153-62.
12. Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med. 2000; 191:593-602.
13. Boeing H, Jedrychowski W, Wahrendorf J, Popiela T, Tobiasz-Adamczyk B, Kulig A. Dietary risk factors in intestinal and diffuse types of stomach cancer: a multicenter case-control study in Poland. Cancer Causes Control. 1991; 2:227-33.
14. Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolos C, et al. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol. 2003; 199:36-40.
15. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process. Cancer Res. 1992; 52:6735-40.
16. Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, et al. Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia. J Gastroenterol. 2002; 37:94-100.
17. Faller G, Kirchner T. Immunological and morphogenic basis of gastric mucosa atrophy and metaplasia. Virchows Arch. 2005; 446:1-9.
18. Graham DY, Lew GM, Klein PD, Evans DG, Evans DJ, Saeed ZA, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer: a randomized, controlled study. Ann Intern Med. 1992; 116:705-8.
19. Hirayama F, Takagi S, Iwao E, Yokoyama Y, Haga K, Hanada S. Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils. J Gastroenterol. 1999; 34:450-4.
20. Joossens JV, Hill MJ, Elliott P, Stamler R, Lesaffre E, Dyer A, et al. Dietary salt, nitrate and stomach cancer mortality in 24 countries. Int J Epidemiol. 1996; 25:494-504.
21. Kato S, Tsukamoto T, Mizoshita T, Tanaka H, Kumagai T, Ota H, et al. High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production. Int J Cancer. 2006; 119:1558-66.
22. Lauren P. The two histological main types of gastric carcinoma: diffuse and intestinal-type. ActaPatholMicrobiol Scand. 1965; 64:31-49.