Research Paper on Gastric Cancer

Definition of Gastric Cancer

Gastric cancer, also known, as stomach cancer is a disease in which malignant or cancer cells form in the lining of the stomach usually in the upper part of the abdomen and just below the ribs (National Cancer Institute [NCI]).

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Brief Introduction

The lining of the stomach is made up of 5 layers, that is, from the innermost, there is mucosa, submucosa, muscle, subserosa and serosa. Stomach cancer begins in the mucosa and spreads to the outer layers as it grows. The disease is not only the second prevalent cause of cancer-related deaths but also the fourth prime cause of cancer (McLean MH & El-Omar EM, 2014). NCI estimated that there were approximately 28,000 new cases of stomach cancer in 2017 with 1.7 per cent occurring in the United States.

Cancer exists in five stages as Stage 0, Stage I, Stage II, Stage III and Stage IV in order of severity. There are many causes of gastric cancer. Some are natural others human-caused. They include smoking, overweight, type -A blood group, genetic heredity, exposure to asbestos, ulcer surgery, eating smoked or salty foods etc.

Symptoms of gastric cancer are not distinctive from early stages to advanced stages, and the symptoms may indicate other health conditions. It is difficult to detect the disease at early stages until it reaches advanced stages making treatment difficult. Some of the sign and symptoms in the early stages include indigestion and stomach discomfort, dilated feeling after eating, mild nausea, loss of appetite heartburn etc. For advanced stages: vomiting, blood in the stool, weight loss, stomach pains etc.

There are various treatment options available, but their effectiveness largely depends on the stage of cancer and the general health of the patient. Treatment options are surgery, chemotherapy and radiotherapy.

Under normal circumstances, surgery can be used to remove a cancer tumour. However, in cases where metastasis has occurred to other organs, surgery is not efficient. As a result, anti-cancer chemotherapies and radiotherapies are needed to treat cancer patients. Chemotherapy involves the development of anti-cancer agents, injections or drug treatments. Even though these therapies have proved to be useful in the treatment of cancer cases, there are side effects associated with them.

Cancer cells usually grow fast. Targeted therapies try to suppress the growth or kill the fast-growing cells. These drugs typically move throughout the body, and as a result, there are high risks of affecting normal, healthy fast-growing cells (American Cancer Society, 2018). Damage to these cells causes adverse side effects in extreme cases. For instance, many anti-cancer agents induce cell-cycle associated-DNA damage.

Naturally, cell-cycle checkpoints are charged with the maintenance of genomic integrity. They respond to DNA damage and further progression of the cell cycle. Normal cells repair damaged DNA during G1-arrest, and efforts to correct these problems may slow growth and induce cell death. However, cancer cells often have deficient G1-arrest. This may further enhance the proliferation of cancer cells. Therefore, these cells largely depend on G2-arrest to allow the cell to repair damaged DNA before entering mitosis. This means defects in the G2-arrest checkpoint may allow a damaged cell to enter mitosis and undergo apoptosis. This poses a challenge when carrying out chemotherapy (Wilkin, 2009).

Most therapies target WEE1 nuclear kinase, a family of protein kinase responsible for controlling these checkpoints. WEE1 responds to chromatin synthesis in response to DNA damage. Once DNA is damaged, WEE1 through CDK1 Tyr15 phosphorylation inhibits the cell cycle in the S/G2 phase (as shown in Fig 1).

Fig 1: Involvement of Wee1 in G2-M regulation and possible consequences of Wee1 inhibition in p53-mutant cells upon exposure to DNA damage. p53 wild-type cells have the opportunity to arrest the cell cycle at the G1 checkpoint to repair damaged DNA. Cells with a defective p53 pathway rely mainly on DNA repair at the G2 checkpoint (Jill et al., 2017).

Targeting WEE1 kinase during molecular therapy for gastric cancer also has adverse side effects. It causes mitotic infidelity, chromosome loss (DNA damage) and apoptosis (commonly referred to as mitotic catastrophe). Preclinical and clinical trials have been carried out to try and reduce these effects. Among the remedies suggested include use of WEE1 inhibitors. For instance, AZD1775 (formerly MK-1775) has useful checkpoint inhibitory activation. There are even further suggestions of combining AZD1775 with S-phase toxins such as DNA cross-linking agents, nucleoside analogues or inhibitors of DNA metabolism, or topoisomerase poisons chemo-sensitising activities to realise more efficient inhibitory activation. Based on toxicity studies from a Phase I of the AZD1775 trial, it is safe to combine AZD1775 with a variety of chemotherapy agents to treat solid tumours (Do et al., 2013; Khanna, 2015; De Witt Hamer et al., 2011).

Effects of WEE1 on Proliferation and Motility of Gastric Cancer Cells

Overexpression leads significant increase in WEE1 cell viability as well as an increase in gastric cancer cell invasion and migration (Kim et al., 2014). Besides, overexpression of WEE1 has been reported in several cancer patients such as malignant melanoma, breast cancer, osteosarcoma and glioma (Magnussen et al., 2012).

A high WEE1 expression is also associated with massive lymph node metastasis of male gastric cancer patients (Kim et al., 2014; Hye-Young et al., 2016). Male gastric cancer patients with lymph node metastasis usually in stage 1-3 show a correlation with poor prognosis and higher WEE1 expression. Most patients with High WEE1 expressions, also referred to as overexpression have poor survival probability.

When human Gastric cancer cell lines are treated with AZD1775, their sensitivity to the inhibitor corresponds with WEE1 expressions in gastric cancer cells. WEE1 high-expressing cells are more sensitive than WEE1 low-expressing cells.

Solutions to Proliferation and Motility of Gastric Cancer Cells

One of the practical solutions of reducing invasion and migration of gastric cancer cells is ablation of WEE1. This has been supported by a decrease in WEE1 expression as well as inhibited cell viability in WEE1 siRNA transfected cells. (Kim et al., 2014). Furthermore, AZD1775 significantly reduces cell viability in gastric cancer cells in a dose-dependent and time-dependent manner (Kim et al., 2014; Hye-Young et al., 2016).

Combined treatment with AZD1775 and anti-tumour agents, 5-FU (5- fluorouracil) and Paclitaxel (PTX) is another suggested treatment criterion. When WEE1 inhibition and DNA-damaging agents are combined they promising antitumour effects and manageable side effects. Combined treatments show more significant inhibition of cell viability than treatment with the single agents alone. (Geenen & Schellens, 2017; Chaudhuri et al., 2014).

Conclusion

Understanding the role of WEE1 in multiplication and motility in gastric cancer as well as targeting WEE1 kinase in chemo and radiotherapy can help in controlling, managing, treating and subsequently curing gastric cancer.

References

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