Abstract

Your stomach's inner lining is typically where cancer cells start when you have stomach cancer, also known as gastric cancer. As the cancer progresses, it infiltrates your stomach walls more deeply. Early accounts of potential stomach cancer were documented in the Ebers papyrus, which dates back to 1600 BC, and in the Hippocrates reports, which Galen related from Rome in the second century AD. According to legend, Hippocrates was the 18th successor of Aesculapius as Master of the Greek Medical School. He lived in Greece in the fourth century BC, between Kos and Athens. He was the first to use the terms "cancer" and "carcinoma" (Karkinos and Karkinoma in Greek), but he thought that this disease entered the body through the skin and spread to soft tissues and interior organs. Because corpses could not be used for medical anatomical investigations in Egyptian, Greek, or Roman cultures, Hippocrates had firsthand experience with only exterior cancers. According to GLOBOCAN 2022 data, GI cancers accounted for 24.6% of all new cancer cases globally, causing over one-third (34.2%) of all deaths and imposing a significant cost on human health. The location and stage of stomach cancer determine the available treatment choices. When creating a treatment plan, your healthcare professional also considers your preferences and general health. Treatments for stomach cancer include immunotherapy, targeted therapy, radiation therapy, chemotherapy, surgery, and palliative care. Pharmaceutical formulations made up of particles of a nanometer range are called nanoemulsions. Because of their hydrophobic core, they can encapsulate medications that are not very soluble in water. They are a steady and secure alternative for drug delivery because they are also made of safe gradient excipients. The topic of cancer treatment has existed for several decades. Low solubility, multidrug resistance (MDR), and unspecific toxicity are the main reasons why medications created to treat this illness don't always work or fail. It may be possible to treat tumours safely and effectively with nanoemulsions. We evaluate the current status of stomach cancer, potential treatments, and underlying causes in this article.

Keywords

Introduction

Around 1500 BCE, cancer was first discovered. Since then, several strategies have been put forth and used to combat it, but no notable progress has been made. Furthermore, gastric cancer (GC) can originate from germs, the environment, or the host. Compared to other ethnic groups, some may be more susceptible to it. Additionally, one of the most significant poor prognostic factors for GC is that it is a type of localized tumour with locoregional metastases. Since most GC patients are first discovered at an advanced stage, it is challenging to cure. In clinical practice, apart from early diagnosis, it is also necessary to diagnose cancer at varied stages and to ensure effective planning of surgical resection. Gastric cancer is the fifth most commonly diagnosed cancer and the fourth most common cause of cancer-related deaths globally. Over the past three decades, the incidence of stomach cancer has decreased and varies significantly by region. Age, Helicobacter pylori infection, hereditary disorders, and eating habits are risk factors. Although screening programs are rare in Western nations, they may be beneficial for high-risk populations. Intestinal and diffuse-type tumours are the two main histologic kinds of gastric cancer. Although proximal gastric cancers are becoming increasingly common, distal stomach cancers (antrum and body) are more common. Due to the delayed onset of symptoms, stomach cancer is frequently diagnosed at an advanced stage. The preferred diagnostic procedure is endoscopy, which enables tissue sampling, visual examination, and early tumour removal. The cornerstone of curative treatment is still gastrectomy, with the extent of resection depending on the size and location of the tumour. Additionally, a complete lymphadenectomy is advised. Perioperative chemotherapy and maybe radiotherapy improve patient outcomes. Immunotherapy and tailored drugs have recently greatly enhanced the prognosis of individuals with actionable mutations. Even with these improvements, stomach cancer still has a dismal prognosis overall, particularly in less-developed areas. However, there are currently insufficient methods for both diagnosing and treating GC. However, one of the most well-known approaches to treating GC to date has been thought to be surgery. In this situation, more creative methods are needed to address GC. The diagnosis of GC consists of three steps: (1) imaging of the tumours (i.e., routine systemic and locoregional imaging), (2) endoscopy-based or GC-associated biomarker-based tumour detection in the primary stage, and (3) GC circulating tumour cell (CTC) detection (1–5). Nanomedicine is a key contender for therapeutic applications due to its remarkable physicochemical properties. Nanomedicine is the word used to describe the use of nanotechnology in medical applications. Furthermore, a variety of innovative drug delivery technologies, including microspheres, microbeads, and nanoparticles (NPs), have been used to treat gastrointestinal disorders; of these, NPs have attracted the greatest attention due to their nano size. Additionally, they are used extensively in the diagnosis, imaging, and treatment of a variety of illnesses. Because of the special material qualities that manifest at the nanoscale, NPs containing bioactive compounds offer numerous advantages as theranostics in cancer. NPs can be used as a therapeutic agent for a variety of cancer types (such as GC) in addition to imaging. Furthermore, these NPs can mitigate a number of chemotherapy-related side effects in the treatment of GC, perhaps increasing the treatment's effectiveness. Liposomal doxorubicin (DOX) formulation (also known as Doxil), liposomal paclitaxel, albumin-bound paclitaxel (Abraxane), and other drug-loaded NPs have all been utilized to treat GC. Additionally, the usage of NPs is beneficial since it may reduce side effects and improve therapy effectiveness. The efficiency of GC treatment is increased by these nanodrugs, which also lessen the negative effects of the chemotherapeutics they load. Furthermore, there has been a lot of interest in theranostic nanoparticles (NPs), which are multifunctional nanosystems created by combining therapeutic and diagnostic properties into a single NP (6).

       
           
       
Fig.1: Gastric Cancer.

Pathophysiology Of Gastric Cancer

There are two primary histologic variations of gastric adenocarcinoma, under the Lauren classification. The intestinal type is the most prevalent variation; it resembles other intestinal adenocarcinomas in appearance and is distinguished by gland production. Diffuse-type gastric cancer is less prevalent and usually does not have gland development or intercellular adhesion molecules. Signet-ring cells may be linked to intestinal-type malignancies.
Intestinal cancers most likely have a complex molecular cause. The most frequent cause of carcinogenesis is H pylori, and there is evidence that these lesions gradually develop from dysplasia to cancer. Cancer frequently develops after precancerous lesions and cancer-predisposing diseases such as gastric ulcers, atrophic gastritis, and pernicious anaemia. No distinct precancerous lesions have been found in diffuse-type tumours (7).

Epidemiology Of Gastric Cancer

Globally, gastric cancer is the fourth most deadly and fifth most prevalent type of cancer. Despite a decrease, East Asia and low-resource nations continue to have far higher incidence and fatality rates. In the United States, it is anticipated that 26,890 new cases of stomach cancer will be identified in 2024. Males are more likely than women to develop gastric cancer. Better diet, access to clean water, and early detection and treatment of H pylori infection have all contributed to a significant decrease in the incidence of distal gastric malignancies in developed nations. On the other hand, GEJ and proximal gastric cancer rates have been rising. Intestinal and diffuse-type gastric cancer rates have decreased overall, with the decrease for intestinal-type cancers being more pronounced. Consequently, a sizable fraction of all stomach malignancies is now diffuse-type tumours. While diffuse-type cancers affect both sexes equally, intestinal-type tumours are more common in men. The incidence of stomach cancer is minimal in India. It is one of the five most prevalent types of cancer. It matters that incidence varies by region. Among Indian men and women aged 15 to 44, it is the second most frequent cause of cancer-related fatalities. India has a low rate of Helicobacter pylori carcinogenesis. The presentation's advanced state is concerning. Clinical and basic research conducted in India shows results and standards of treatment that are similar worldwide. Healthcare policy administrators continue to face significant hurdles due to the big population, sociodemographic profile, and health expenditure issues. Improved healthcare delivery and the best possible results are anticipated with the recent establishment of the National Cancer Grid, the integration of national databases, and the development of the social identification database Aadhaar by the Unique Identification Authority of India. About 5% of all cancer cases in India are stomach cancers, making them the fifth most common type of cancer, according to the Indian Council of Medical Research (ICMR) (8,9).

Etiology Of Gastric Cancer

Although gastric tumours are mostly sporadic, there is a hereditary or familial component in 5–10% of cases. The following are the main risk factors for stomach cancer: Pylori Helicobacter: H pylori infections that are persistent and recurrent are known risk factors for gastric cancer. The pathogenesis is probably significantly influenced by host characteristics, other risk factors, and the length of the infection. Epstein-Barr virus: Typically affecting the proximal stomach, this viral infection has been increasingly linked to gastric cancer. Risk factors include a diet low in vitamins A and C, smoking, consuming a lot of smoked or cured foods, drinking water that is contaminated, consuming N-nitroso compounds, and consuming a lot of salt (salt-preserved foods). Obesity: Proximal gastric and GEJ cancer risk is increased by a high body mass index. Smoking: Smoking raises the risk of stomach cancer, especially in men. Chronic gastroesophageal reflux disease is linked to an increased risk of GEJ adenocarcinomas. Furthermore, bile reflux into the stomach, which occurs in patients following some gastric procedures, raises the risk of gastric cancer. Environmental factors: Coal, metal processing, tin mining, and rubber production all raise the risk of stomach cancer. Host factors: People with type A blood, especially those with the diffuse form, are around 20% more likely to develop gastric cancer than people with blood groups O, B, or AB. The risk of intestinal-type gastric cancer is increased by up to six times in cases of pernicious anaemia and chronic atrophic gastritis. For additional information, please refer to the complementary resources "Pernicious Anemia" and "Atrophic Gastritis,". Hypertrophic gastropathy, gastric polyps, and benign gastric ulcers are other disorders linked to an elevated risk. Protective factors: Eating a lot of fruits, vegetables, and fibre probably helps prevent stomach cancer. Genetic associations: Genetic disorders are linked to a subset of stomach malignancies, including The lifetime risk of hereditary nonpolyposis colon cancer, which is primarily intestinal, is 13% (1,8,10–12).

Diagnostic Evaluation Of Gastric Cancer

The main diagnostic procedure for patients with symptoms suggestive of stomach cancer is an upper endoscopy. Upper endoscopy has the crucial benefit of direct tissue diagnosis by biopsy of esophageal, gastric, or duodenal abnormalities, despite being more intrusive and expensive than conventional barium or gastrografin swallow examinations. To greatly increase diagnostic accuracy, each suspicious stomach ulcer should be biopsied several times; sensitivity rises from about 70% with a single biopsy to 98% with seven biopsies. It is crucial to meticulously record the lesion's location, dimensions, and features. If more subtle mucosal lesions are suspected, further methods like chromoendoscopy and narrow-band imaging should be used. Additionally, if atrophic gastritis, H pylori infection, or other conditions are suspected, several mucosal biopsies must to be taken. In high-incidence regions like South Korea and Japan, upper endoscopy has been very successful in identifying early-stage stomach cancer, which has increased the cure rate after resection. In other areas, meanwhile, this use is less widespread. For a more thorough evaluation of stomach cancer lesions, an endoscopic ultrasonography (EUS) is frequently necessary after an upper endoscopy. EUS plays a key role in assessing the perigastric lymph nodes, which can be biopsied using EUS-guided fine-needle aspiration and identifying the tumour's T stage. With confidence ranges of 0.78 to 0.91 and 0.85 to 0.93, respectively, EUS's pooled sensitivity and specificity for differentiating between T1 and T2 tumours are 0.85 and 0.90. This distinction is important because endoscopic resection may be an option for T1 gastric tumours. However, the expertise of the operator greatly affects the accuracy of EUS, and less experienced clinicians may have less accurate assessments of stomach wall invasion (13,14). Staging Evaluation: To rule out metastases and assess surgical resectability, chest and abdominal imaging are required for thorough preoperative staging. To rule out gross metastatic illness, early abdominopelvic computed tomography (CT) is used. With an overall accuracy ranging from 42% to 82%, it is limited in its ability to evaluate T and N stages and identify minor peritoneal metastases. If malignant ascites are detected, paracentesis is advised, and a biopsy of any suspicious solitary or oligometastatic areas should be carried out. For better examination, chest CT is favoured over plain radiography. When the initial staging is negative for metastatic disease, resectability may be evaluated using positron emission tomography in conjunction with computed tomography. Carcinoembryonic antigen, cancer antigen 125, carbohydrate antigen 19-9, and cancer antigen 72-4 are examples of serum markers that have little diagnostic utility and can be raised as a result of other illnesses. For individuals with potentially curable illnesses, staging laparoscopy with peritoneal washings for cytology is recommended before beginning chemotherapy. Up to 40% of patients may have peritoneal disease during diagnostic laparoscopy; this condition may not be diagnosed by traditional preoperative imaging but may be discovered by direct biopsy or cytology from peritoneal washings. Patients who have peritoneal disease are usually not operated on since they are thought to have metastatic disease. A tiny percentage, though, might be candidates for intraperitoneal chemotherapy and severe cytoreduction (15–19).

Treatment Of Gastric Cancer

Endoscopic resection, surgery, chemotherapy, radiation, and targeted therapies are among the therapeutic options utilized for stomach cancer. These methods are frequently mixed according to the patient's characteristics, tumour location, and stage. Only malignancies confined to the mucosa or the very superficial submucosa without significant risk factors are suitable candidates for endoscopic procedures. The majority of patients who have tumours larger than T2 or who show any signs of nodal involvement should get chemotherapy before surgery. Palliative chemotherapy is recommended for patients with advanced or incurable malignancies. Usually, radiation is only used for palliation or in cases where surgical resection is not sufficient. Each modality is covered in the section that pertains to it(20).

5. Gastric Cancer Treatment Using Nano Delivery

Limited circulation time, low concentrations within the targeted treatment area, decreased water solubility, and toxic side effects from uneven biodistribution all hinder conventional chemo-treatment of cancer. These issues lower the treatment's overall efficacy and have a detrimental effect on patient morale. Therefore, a better pharmacokinetic strategy for addressing the shortcomings of existing combination medicines is the use of drug systems functioning at the nanoscale. Nanoparticles (NP) are colloidal carriers that can be manufactured or natural and range in size from 1 to 1000 nm. High specificity, enhanced efficiency, superior stability, and little overall toxicity for the patient are the main benefits of employing NPs in the delivery of cancer treatment medications (21). Through active or passive methods, nanotechnology aids in the targeted treatment of individual tumours. To specifically target and eliminate cancer cells without affecting or impairing the nearby noncancerous tissues, surface-modified nanoparticles (NPs) loaded with anticancer medications have been used. Additionally, NPs have been used to treat GC by modifying the conventional methods of cancer treatment in addition to using novel strategies. To manage GC, many NP forms have been used either alone or in combination (22,23).

       
           
       
Fig.2: Treatment of Gastric cancer with Nanoparticles.

17. Gastric Cancer Targeted Drug Delivery Systems Using Nano Emulsions

The primary method for delivering various medications, nucleic acids, and imaging agents is nanoemulsion. It has been widely employed for imaging and cancer therapy diagnostics because of its appealing qualities. However, by altering the surface and encasing potent anti-cancer chemicals, nanoemulsion is created to serve a variety of purposes. targeted the surface charge with a targeted ligand can modify the surface modification in a nanoemulsion. It is possible to load medications, contrast agents, and imaging agents into the emulsion's core. By 2030, the International Agency for Research on Cancer (IARC) projects that there will be 13.2 million cancer-related deaths and 21.4 million new cancer cases. With a predicted 67% rise in cancer incidence for the elderly 65 and older, this adjustment significantly raises the total number of malignancies diagnosed annually. Because of its self-assembled nature, which makes it naturally responsive to its immediate environment, and its versatility in terms of component combinations that can produce structures with multiple responsive functionalities, oil-in-water (o/w) type nanosized emulsion (NE) is the best option among the various nanocarriers that are currently available, including different nanoparticles, liposomes, niosomes, micelles, lipoproteins, and various nano assemblies, that have the potential to deliver to tumour tissue. The morphological and physiological distinctions between cancerous and healthy cells can be used to determine how well passive tumor-specific medication delivery works. For instance, molecules and nano emulsions can readily enter the extravascular spaces due to the leaky vasculature of cancer cells (EPR effect), but they are unable to exit the tumor due to the cancer cells' immature lymphatic drainage. Actively targeting overexpressed receptors as molecular targets is an additional strategy for efficient tumor-specific medication delivery. Tumor cells overexpress a high number of tumor-specific receptors, which can be utilized as targets to deliver lethal chemicals into tumors, because rapidly developing tumors require a greater quantity of various minerals and vitamins than normal cells. Currently, the majority of them are employed as tumor biomarkers in clinical settings. EGFR, PRSS8, FOLR1, ALDH1, O-B2, VPAC1, IGF-1R, and mRNAs are a few examples of biomarkers used to identify different types of cancer. The conjugation of compounds that can selectively bind to the overexpressed receptors using appropriate linkers that demonstrate selective drug delivery to the tumor site through receptor-mediated endocytosis can be accomplished by taking advantage of the difference in the rate of expression of these biomarkers in normal and tumor tissues. The flexibility of nano emulsions allows for the local or systemic delivery of macromolecules, such as antigenic proteins and peptides, which produces strong humoral and cellular antigen-specific immune responses to tumours. The immune system's primary sentinel in the fight against cancer was a unique kind of immune cell known as a T cell. The term "immune surveillance or immunosurveillance" was created as a result of this elaboration to refer to the idea that the immune system is constantly vigilant against cells that have transformed.
The idea that IFN-gamma and lymphocytes stop the growth of primary tumors and influence tumor immunogenicity has made the immunosurveillance theory controversial. The authors demonstrated that lymphocytes and the immunological stimulator IFN-gamma work together to prevent the development of both spontaneous and carcinogen-induced cancers using genetically modified mice without a functioning immune system. Therefore, an immune response may target even cancers that have eluded detection. Long circulation durations and enhanced cellular absorption by APCs are two benefits of using nano emulsions for vaccine administration. When compared to free LBT, the PEGylated LBT–OA–nanoemulsion demonstrates a noticeably higher concentration of LBT in the lung tumor tissue. It also shows a longer life period and a stronger growth inhibitory impact than free LBT in both heterotopic and lung metastatic tumor models (24–27).

• Drug Delivery System (Nanoemulsion)

Pharmaceutical formulations known as nanoemulsions are made up of particles that are nanometers in size. Their hydrophobic core nature allows them to encapsulate medications that are not very soluble in water. They are also made with safe gradient excipients, which makes them a reliable and secure medication delivery method. The topic of cancer treatment has been around for a few decades. The major reasons why medications created to treat this illness don't always work or fail are limited solubility, multidrug resistance (MDR), and nonspecific toxicity. Nanoemulsions could be the key to safe and effective tumour treatment. In addition to addressing issues with water solubility, these formulations offer precise targeting to cancer cells and may potentially be made to overcome MDR. Different types of ligands can be used to modify nanoemulsions to target elements found on the surface of tumour cells or to get beyond MDR processes. Many researchers in various fields are investigating multifunctional nanoemulsions, mostly for the treatment of various cancers. These investigations all show that nanoemulsions are effectively absorbed by tumor cells, inhibit tumor growth, remove toxicity to healthy cells, and stop cancer cells from migrating to other organs (28). Nanoemulsions are one of the more recent nano-drug delivery systems being actively investigated for the treatment of brain cancer. Certain characteristics of these systems make them appealing to medication delivery methods with strong brain delivery potential. The oil droplets' modest size—typically less than 100 nm—provides natural stealth characteristics. Through the synergistic effects of several components, the design of a functional and multifunctional nanoemulsion may allow for improved medication transport across the blood-brain barrier. Since many anti-cancer medications are extremely hydrophobic, they can be easily added to nanoemulsions. Both hydrophilic and hydrophobic medications can be loaded onto these adaptable nanocarriers. It is also possible to easily include a combination of anti-cancer medications. To maximize brain uptake, they can also be customized to include functional and multifunctional qualities. As carriers for extending the drug release following intramuscular and intratumoral injection (w/o systems) and as a way to improve the lymphatic system's ability to carry chemotherapeutics, nanoemulsions may also be appropriate substitutes in cancer treatment. The ability of positively charged nanoemulsion systems to interact more effectively with negatively charged cell surfaces has been investigated concerning the potential delivery of oligonucleotides to cancer cells(27,29).

DISCUSSION AND CONCLUSION

Among the many causes of gastric cancer, our review articles provide an overview of its epidemiology, pathogenesis, diagnostics, and alternate therapy. Even though medications (such as nanoemulsion) and other therapies can be used to treat gastric cancer, our research indicates that additional clinical trials are necessary because of the intricacy of this disease. There should be more randomized controlled trials for the treatment of gastric cancer. In the future, we plan to carry out an initial investigation into gastric cancer. In our state or country, counseling-based research will assess patients' physical and mental health and provide more accurate information about gastric cancer and its treatment in the future with the assistance of our colleagues.

Ethical Statement

Be truthful and uphold a high standard of behaviour in all of our interactions and work-related activities. Let's act and speak with integrity.

ACKNOWLEDGEMENT

The authors would like to thank, Azad Institute of Pharmacy & Research (AIPR), Lucknow, U.P, India & B.N. College of Pharmacy, Lucknow, U.P, India for extending their facilities.

Conflict Of Interest

The authors attest that they are free of any known financial or personal conflicts of interest that could taint this study's findings.

Informed Consent                                          

Using websites, review articles, and other sources to produce research content.

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