INTRODUCTION
Gastric cancer (GC) is the fifth most common cancer worldwide and the 4th leading cause of mortality[1]. GC is a malignancy that arises in the area between the esophagus and pylorus, and it most commonly arises from glandular cells. The formation of GC is a slow process that occurs as a precancerous lesion steadily worsens over time. It is a series of histopathological changes in which gastric mucosa undergoes atrophic gastritis and progresses to intestinal metaplasia, dysplasia, and eventually, carcinoma[2].
The most common way in which GC is characterized is based upon histology via the Lauren classification system: (1) Well-differentiated intestinal; (2) Poorly-differentiated diffuse; and (3) Mixed[3]. Further distinction may be included dependent upon the presence of molecular biomarkers. The hallmarks of GC share similarities with many cancer pathways, some of which include proliferative signaling in the absence of external growth signals, evasion of growth suppressors, resistance of apoptosis, induction of angiogenesis, and invasion with metastasis[4]. These mechanisms involve complex, integrated pathways with multiple proteins and enzymes that play a major role in pathogenesis.
The development of GC is multifactorial, affected by family history, lifestyle, diet, socioeconomic status, and infection. Infection with bacterium Helicobacter pylori is one of the most common factors seen in patients with GC. Infection can induce a carcinogenic effect through cytotoxin-associated antigen A pathogenicity islands that become pathogenic by activating a signaling cascade via Src homology region phosphatase 2, Abl or Src kinases[5]. This conveys the convoluted mechanism of pathogenesis, enlisting many different pathways to cause disease. Additionally, daily diet is linked to GC due to its effect on the gut microbiome. Composition of the gut microbiome varies significantly between individuals yet was found to have even more drastic differences between individuals with GC and healthy individuals[6]. This potentiates the effect that food and supplements may have on the body, to cause harm but also to possibly heal.
INTEGRATION OF TRADITIONAL MEDICINE AND MODERN MEDICINE
Traditional Chinese medicine (TCM) has been used for thousands of years. TCM focuses on psychological and physical approaches with herbal products to address health problems, and it has a key role in integrative medicine[7]. TCM is characterized by a holistic view of medicine, recognizing the close relationship between the human body and its environment. Disease is described by imbalances within the body, not a pathogen itself. TCM recognizes the human body by way of cybernetics and system discrimination[8]. TCM works to identify imbalances within the body and develops a treatment plan to restore health and harmony. Within this framework, TCM focuses on prevention of disease.
TCM believes that there should be a precise therapy targeting a specific cause in order to restore balance within the body. However, there are many factors that influence balance within the body in system discrimination. There have been studies that show combining modern drugs with herbal medicine would increase its effect, as it may target more specific and integrated pathways to restore balance. For example, it was found that combining herbal medicine in traditional treatment of coronary artery disease may increase the effect rate from 45.5% to 87.3%[8]. This demonstrates that TCM may supplement modern medicine in treatment and prevention of disease, as it helps target specific pathways disrupting the body’s balance.
Pharmacology has evolved over the years, from simple drug discovery to network pharmacology (NP), to acknowledge the importance of integrating traditional knowledge of nutraceuticals with state of the art technologies. NP was founded to address the complex interactions of pathways within the body, working to understand drug interactions with these pathways within a cell[9]. This revolutionary change to drug development was made possible due to the 20th century genome sequencing, which led to target-based pharmacology. Patwardhan[10] explain the evolution of drug discovery with the modern omics technologies in their paper, stating that most diseases are the dysfunction of several proteins in multiple metabolic pathways, calling for the need to address more than one target for holistic management. This encouraged pharmacists to explore natural sources, such as nutraceuticals, to integrate traditional knowledge with modern technology for drug development.
This article written by Micucci et al[11] proposes a combination of TCM and modern medicine in the realm of GC. The integration of TCM’s herbal compounds and formulations within GC may prevent the disease itself, enhance treatment by reducing side effects from traditional treatment plans, and prevent recurrence after cure by focusing on system differentiation. GC is a heterogenous disease with multiple subtypes, each with distinct properties and various effects on patients[12]. These effects are dependent upon the many pathways involved in the early stages of GC development, listed in Micucci et al’s review as potential targets for preventative strategies[11]. The article addresses the Wnt/β-catenin signaling pathway, oxidative stress biomarkers (malondialdehyde, superoxide dismutase, and glutathione peroxidase), programmed death ligand-1 (PD-L1), hypoxia-induciblefactor-1, epidermal growth factor receptor (EGFR), interferon-gamma receptor and toll-like receptor 4, and nutritional and immunological parameters such as albumin and immunoglobulins. The author illustrates many different TCM compounds and formulations that work to inhibit these pathways. For example, the TCM formulation Banxia Xiexin decoction was shown to inhibit GC cell proliferation by inhibition of the Wnt/β-catenin signalling pathway. This mechanism was shown to stop invasion of GC cells, helping to prevent metastasis. The many examples listed by the author demonstrate that the addition of modern NP with TCM’s use of nutraceuticals may better target the complicated interaction of pathways within GC. This can lead to enhancement of prevention and treatment of GC. This is all made possible due to the modern omics technology and the push towards precision medicine.
TCM AND NUTRACEUTICALS IN GC
“Nutraceuticals” was a term coined in the late 20th century to describe the components of food that have a positive impact for health and well-being[13]. However, the principle of nutrition in the realm of pharmaceuticals was not a novel topic. The Hippocrates philosophy connected human health with food in the 19th century by stating “let the food be thy medicine and thy medicine be the food”. And dating back thousands of years, the concept of food as medicine is rooted in TCM’s theory of balance within the human body. Historically, skepticism surrounds the landscape of TCM and the use of nutraceuticals as a form of medical treatment due to a lack of sufficient research and evidence. In modern times, chronic conditions and aging are prominent medical challenges. This medical climate is promoting a paradigm switch from treatment to prevention. This has caused an uprising in nutraceuticals as certain diets and natural compounds aid in the prevention and treatment of chronic diseases and anti-aging.
Many GCs are diagnosed in advanced stages, in which the treatment is limited to chemotherapy. The preferred approach in current guidelines suggests perioperative chemotherapy or postoperative chemotherapy plus chemoradiation; however, there is no gold standard therapy used in GC, and treatment options are highly dependent upon the physician’s preferred course of action[3,14]. As with many other cancers, immunotherapy has also played a key role in GC. Assessment of tumor tissue for expression of DNA mismatch repair, PD-L1, and human EGFR 2 (HER2) allows for the complementing of systemic treatment with drugs that target specific pathways in tumorigenesis[15]. This has allowed treatment to target more specific genetic and molecular features. Though due to the multifactorial nature of GC and the mechanism in which GC activates multiple pathways that lead to tumorigenesis, there is more work that needs to be done to develop a more cohesive treatment plan.
Modern medicine has made recent advances for therapeutic targets in GC. Characterization of various pathways via next generation sequencing has helped scientists and physicians understand GC on a molecular level. Since GC develops slowly, this understanding of GC pathways provides potential targets for preventative strategies. Due to the many involved pathways of GC development, as well as its slow development, this discovery potentiates the benefits from a shift of ideology from not only treatment of GC but also prevention. As Micucci et al[11] indicated in their article, many recent studies have shown the benefit of various nutraceuticals within TCM that help prevent and enhance treatment of GC by targeting specific pathways. More research is required in order to implement the use of these nutraceuticals in GC standard of care. However, omics technology is needed to further explore and understand the various subtypes of GC within each individual patient. Then, the benefits of nutraceuticals can be utilized by targeting distinct pathways that is unique to each patient.
OMICS TECHNOLOGY IN GC
Precision medicine demands a more individualized treatment for each patient, rooted in the belief that each person has unique characteristics in their molecular, physiological, and environmental exposures. Thus, disease will look differently in every person[16]. Personalized medicine has risen in popularity due to the recent application of DNA sequencing and proteomics within medicine. The goal is to optimize efficacy of treatment for each individual using genetic and molecular profiling. Micucci et al[11] emphasize the heterogenous nature of GC by expanding upon the multiple proteins and biochemical pathways used in tumorigenesis; however, the article does not elaborate upon the various subtypes that are emerging within GC due to modern technology, which may further benefit the development of targeted drugs and the supplemental use of nutraceuticals in prevention, treatment, and recurrence.
One factor within the realm of GC that fails to encompass its complex nature is the classification system. With solely relying upon histological differences for classification, the heterogeneity of the disease is lost, and therefore, it is difficult to individualize treatment plans. The further characterization of GC in the 1980’s with the discovery of HER2 and vascular endothelial growth factors helped target therapy treatment options; yet targeting a single gene has limitations[17]. As the authors displayed in their review, there are many different biochemical pathways and proteins that lead to the development of GC. Therefore, omics technology will help contribute to a better characterization of GC and further the field of personalized medicine by understanding certain GC subtypes and their paths to malignancy.
It has been found that response rates to conventional chemotherapy treatment plans regarding GC vary from 20%-40%, demonstrating a wide range of responses when GC is treated the same among individuals[18]. Additionally, Cheng et al[19] found that various oncogenic pathways are downregulated with varying frequencies in GC. Yet despite this evidence, many GCs are treated the same. Enrichment of the classification of GCs into biological and clinical subtypes may better predict prognosis and improve the treatment plan. Tan et al[18] demonstrated this belief through a study that focused on intrinsic subtypes of GC by investigating cell lines, discovering distinct patient survival and response to chemotherapy based upon its subtype.
Several studies have been conducted that enlist omics technologies to further characterize GC and predict prognosis. Li and Wang[20] clustered GC based upon the activity of 15 biological pathways, including those mentioned by Micucci et al[11] involved in DNA repair and oncogenic signatures, to develop a prognostic model that accurately predicts immunotherapy therapeutic response based upon expression levels of certain genes. Mun et al[21] performed proteomic analysis of tumor tissue that stratified diffuse-type GC by linking somatic mutations to phosphorylation changes in signaling pathways. Another study facilitated precision medicine by establishing a 10-metabolite GC diagnostic model and identified 2 biomarker panels that enabled early detection and prognosis[22]. These studies demonstrate the existence of many different GC subtypes and their variability in prognosis and treatment response. This supports the use of precision medicine in characterizing GC and providing patients with unique treatment based upon their molecular and genetic composition. Additionally, the use of precision medicine can aid in the prevention and recurrence of GC in at risk populations and those in remission.
Other disease processes have seen improvement in patient outcomes due to precision medicine. A study by Soda et al[23] identified a mutation in anaplastic lymphoma kinase (ALK) that drives the proliferation of non-small cell lung cancers. This led to the development of ALK blockers for those patients who demonstrated an ALK mutation. Another example is the development of HER2 inhibitors for the treatment of HER2 positive breast cancers. One of these drugs, trastuzumab in combination with chemotherapy, was found to slow disease progression, increase response rate, and prolong survival time compared to just chemotherapy alone[24]. These outcomes demonstrate that better characterization of disease via omics technology can lead to targeted therapies with NP and better patient outcomes.
As demonstrated, there is ongoing research exploring the different subtypes of GC that surpass the elementary histological classification system. These subtypes have a varying therapeutic response to treatment, yet all GC is still treated similarly. Emerging studies in TCM, as shown in Micucci et al’s review, show various nutraceuticals and compounds that complement GC treatment by helping to prevent disease, prevent recurrence, and improve chemotherapy regiments[11]. More research is needed in order to have strong evidence for the benefits of TCM nutraceuticals in the prevention and treatment of GC. Each patient and each GC are unique. For future direction, precision medicine would be able to individualize treatment for each patient based upon their GC subtype. Nutraceuticals may then be employed to directly target specific pathways in an individual’s GC for optimal treatment of a patient’s disease.
CONCLUSION
There has been an increase in the use of CAM over the last few decades, as more than 30% of Americans are incorporating health care approaches outside of conventional Western medicine[25]. This review by Micucci et al[11] proposes a strong argument for a collaborative approach to GC that integrates TCM chemical and pharmacological profiling with precision medicine and modern technology. The authors propose that nutraceuticals may play a supportive role in chemotherapy and radiotherapy by employing the multi-target approach characteristic of NP, addressing the many metabolic and signaling pathways involved in GC. In doing so, there is a potential to prevent progression of disease as well as enhance the success from traditional treatment plans. Moreover, there is a potential to address not only treatment but also focus on prevention within these pathways to GC. Omics technology has allowed for this new pharmacology approach of NP, as well as a better understanding to the many pathways involved in GC. Micucci et al[11] write a thought-provoking review that has the potential to revolutionize the understanding of GC. However, more research needs to be done to better understand and characterize the different subtypes of GC. The implementation of precision medicine can then be improved by incorporating its use earlier in disease progression with more targeted nutraceuticals based upon the genetic and molecular profile of the patient for both prevention and treatment of GC.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade C
Scientific Significance: Grade B
P-Reviewer: Zhang WY S-Editor: Luo ML L-Editor: A P-Editor: Wang WB
