Journal of Mucosal Immunology Research
Open Access

Gastrointestinal neoplasms; Autophagy; Epigenetics; Tumorigenesis; Chemo resistance; Tyrosine phosphatases; Gastrointestinal cancer; Platelets Tumor microenvironment

Introduction

The liver, gallbladder, and pancreas are gastrointestinal glandular auxiliary organs that are included in the gastrointestinal (GI) system. The lower and upper gastrointestinal systems are made up of the esophagus, stomach, and intestines [1, 2]. GI cancers are among the top ten cancers that cause death globally, with some of them having a high rate of morbidity and prevalence. A spectrum into GI tumour pathogenesis is provided in pan-cancer studies by a thorough analysis of GI cancers, including three compartments of upper GI, lower GI, and accessory organs, using integrative computational methods as well as examining their similarities and differences across anatomic boundaries. Similarities and differences between all or some biologically related cancers are to be found in such studies [3].

Deep insights into the many molecular features of GI malignancies are of great interest due to their high mortality rate. The development, spread, and regulation of cancer are largely governed by altered genetic and epigenetic factors. The epigenetic processes, including DNA methylation, histone modification, and miRNAs, are crucial to the development of tumours. A fundamental process that causes transcriptional perturbations and is a key early event in the development of GI cancer is aberrant hyper- or hypomethylation of DNA. Similar to this, copy number variations (CNVs) are a major cause of hereditary cancer occurrences and are one of the structural abnormalities of the DNA sequence. They include amplifications and deletions of a specific DNA region, both of which are essential for the ensuing pathogenesis of cancer. As a result of the loss of tumour suppressors and the increase of oncogenes during clonal evolution, tumours develop. Non-coding RNAs, including lncRNAs and miRNAs, were also discovered to be deregulated in a variety of cancers, including GI tumors [4]. In GI malignancies, these non-coding RNAs are recognised as crucial regulators. While lncRNAs have a variety of regulatory activities, including gene expression, chromatin remodelling, and posttranscriptional alterations, miRNAs are hypothesised to suppress the expression of their target genes by translational or post-translational control of gene expression. Researching the negative parallel effects of genetic and epigenetic risks on important biological mechanisms, such as genomic instability, cell cycle activation, or the interaction between the tumour microenvironment and the dual function of the host immune system in GI cancers, is a major concern in therapeutic decisions, despite the individual consideration of genetic and epigenetic risks [5].

It should be noted that anomalies in mRNA quantity, methylation, non-coding RNAs, and CNVs, in particular, cause the development of tumours. The main objectives of the current study are to highlight functional pathways and cancer-related genes associated with individual/combinatorial impacts of various biological abnormalities in GI cancers as a pan-cancer study, despite the fact that several studies have concentrated on cancer driver events in GI cancers individually. We chose to apply this idea in our study by introducing a new integrative scoring method and propagation of scores on a signalling network. “Guilt by association” is a principle in the context of genetic associations and systems biology where genes share many molecular and phenotypic traits with their local neighbors [6].

The oesophagus, bile ducts, stomach, colon, pancreas, liver, and rectum were the seven gastrointestinal tumour types of the TCGA that were the subject of our research. We employed the data types for CNV, DNA methylation, and gene expression. The scoring approach was built individually for lncRNA, miRNA, and protein-coding genes using a unique computational technique based on data integration. We disseminated gene scores on a signalling network and identified sub networks to find local interactors of our top-scoring genes. Finally, we conducted several analyses to provide a better understanding of GI cancers, including comparing amplifications/deletions between GI and non-GI cancers and evaluating the regulatory profile of lncRNAs [7, 8].

Material and Methods

The databases of PubMed, the Cochrane Library, and EMBASE (up until December 2021) were all thoroughly searched. The PRISMA checklist was adhered to. RevMan v5.3.0 was used to examine the data.

Discussion

With a 5-year survival rate of roughly 30% for GC and 90% for CRC patients with non-metastatic tumours, but this percentage drops to 11.7% for patients who suffer from distant metastatic spread, the prognosis for alimentary tract malignancies remains appalling, despite advances in detection and therapy [9]. While our understanding of kinase signalling in cancer cells has grown over the years, tyrosine phosphatase signaling’s function in cancer is still not fully understood. Due to the widespread belief that signalling pathways are inactivated as a result of these enzymes’ primary function of dephosphorylating proteins and lipids, they are frequently regarded as tumour suppressors. Contrarily, increased activity of some phosphatases may paradoxically lead to increased rather than decreased phosphorylation of a number of signalling molecules, especially if their targets are repressive. For instance, we have previously demonstrated that the phosphatase PTP1B can help to activate oncogenic signalling by dephosphorylating the inhibitory site of the kinase Src. LMWPTP also targets Src, and leukaemia cells have shown that LMWPTP overexpression causes Src signalling to be activated. Therefore, the increased phosphorylation of downstream oncogenic targets observed in the current study and other studies upon knockdown of LMWPTP may be explained by the removal of inhibitory phosphorylation patterns by phosphatases [10].

Protein tyrosine phosphatases are now being recognised as possible cancer biomarkers and therapeutic targets as a result of this new information. Using this information, we first demonstrate that LMWPTP is overexpressed in gastric, esophageal, and CRC cancers. This suggests that up regulation of phosphatase expression is a common trait among intestinal cancers and raises the tantalizing possibility of a shared target for treatment of these diseases. Second, we observed higher Src and FAK activation in the stomach cancer cell line, which findings were supported by our prior data, when comparing kinase activation in gastric cancer cells with high LMWPTP expression to non-transformed gastric cells with lower LMWPTP expression levels [11].

Next, we questioned if LMWPTP would similarly mediate the interaction of tumour cells with platelets in tumour cells. The increased risk of VTE associated with cancer may be due to various platelet changes that tumour cells produce as well as the ability to change intracellular composition and function. In contrast, platelets and the growth factors they secrete may promote the survival and multiplication of tumour cells as well as aid in the invasion of cancer cells, notably in gastrointestinal cancer. Data from in vivo and ex vivo experiments indicate that platelets surrounding the tumour may support chemo resistance in breast and gastric tumors, be linked to a poor prognosis for gastric cancer patients, and encourage the metastasis of colorectal cancer [12]. Lower gastrointestinal tumour FFPE sections have platelet marker protein CD42b expression; however, it is unknown how closely this correlates with LMWPTP in vivo. We show that platelets influence gastrointestinal tumour cell proliferation and that, at least in an in vitro environment, this mechanism is at least largely dependent on LMWPTP expression in these tumour cells. The proliferation of normal cell lines was not stimulated by platelets; however platelet presence increased the proliferation of stomach carcinoma cells and activated Src and p38. Similar to this, CRC cell lines proliferated more quickly when platelets were present. We then went on to show that LMWPTP plays a significant role in this process using a variety of knockdown models, with knockdown of LMWPTP lowering cancer cell interaction with platelets as well as platelet-mediated proliferation effects.

It’s interesting to note that in this study, co-culturing tumour cells with platelets further boosts their expression of LWMPTP. Although the precise mechanisms causing this process are still unknown, they might involve transcriptional process activation, increased LMWPTP protein stability, or a direct transfer of cells between the two cell compartments. Intriguingly, treatment to tumour cells in vitro can increase LMWPTP (RNA and protein) expression, which is overexpressed in platelets from CRC patients [13]. Extracellular vesicles from cancer cells have been found to modify platelet composition, and the opposite may also be true. It is therefore challenging to determine the ‘chicken and the egg’ in this situation even though platelets and tumour cells clearly influence one other’s signalling and activity. It is tempting to hypothesize that since LMWPTP directly confers a number of tumorigenic properties, upon extravasation of tumour cells into the bloodstream and their subsequent interaction with platelets, a further platelet-mediated up regulation of LWMPTP partially mediates the platelet-induced proliferative advantage. Since integrin 3 on the surface of platelets has been shown to promote phosphatidylinositol 3-OH kinase (PI3K) signalling and the proliferation of hemangioendothelioma cells, our data demonstrate that tumour cells that express LMWPTP directly affect the physical association of tumour cells with platelets. Platelets have also been shown to induce the epithelial to mesenchymal transition when co-cultured with CRC cells [14]. As was demonstrated for breast cancer cells, where PI3K activity and proliferation were enhanced by supernatant obtained from stimulated platelets, platelets also produce significant amounts of growth factors, and it is conceivable that these also contribute to LMWPTP expression and proliferation of tumour cells in situ.

Conclusion

In GI pan-cancer, the study of combinatorial and parallel impacts revealed many routes. An extensive cell cycle-related sub network was produced as a result of biological events occurring simultaneously, whereas smaller or distinct pathways, such as immunological or posttranslational responses, were revealed by biological events occurring separately. We must therefore individually and concurrently investigate abnormalities in order to offer additional insights into cancer biology and recommend better treatments in the clinic.

Acknowledgement

None

Conflict of Interest

None

1. Kim Y, Pritts TA (2017) The gastrointestinal tract.Geriatric Trauma and Critical Care, Springer 7: 35-43.

Google Scholar

2. Haraguchi N (2006) Characterization of a side population of cancer cells from human gastrointestinal system Stem Cells 24: 506-513.

Indexed at, Google Scholar , Crossref

3. Liu Y (2018) Comparative molecular analysis of gastrointestinal adenocarcinomas
33: 721-735.

Indexed at, Google Scholar , Crossref

4. Berger AC (2018) A comprehensive pan-cancer molecular study of gynecologic and breast cancers 33:690-705.

Indexed at, Google Scholar , Crossref

5. Wong CC (2019) Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers Seminars in Cancer Biology. Elsevier 55: 90-105.

Indexed at, Google Scholar , Crossref

6. Zare F (2017) An evaluation of copy number variation detection tools for cancer using whole exome sequencing data. BMC Bioinforma 18:286.

Indexed at, Google Scholar , Crossref

7. Lim SB, Lim CT, Lim WT (2019) Single-cell analysis of circulating tumor cells: why heterogeneity matters.Cancers 11: 1595.

            Indexed at, Google Scholar , Crossref

8. Song B, Ju J (2010) Impact of miRNAs in gastrointestinal cancer diagnosis and prognosis.Expert Rev Mol. Med 12: 165-172.

Indexed at, Google Scholar , Crossref

9. Zhang FF (2016) Metastasis-associated long noncoding RNAs in gastrointestinal cancer: implications for novel biomarkers and therapeutic targets World J. Gastroenterol 22: 8735.

Indexed at, Google Scholar , Crossref

10. Ancrile B, Lim KH, Counter CM (2007) Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev 21: 1714-1719.

Indexed at, Google Scholar , Crossref

11. Bakker (2020) Effects of perioperative intravenous ω-3 fatty acids in colon cancer patients: A randomized, double-blind, placebo-controlled clinical trial.American. J Clin Nutr 111: 385-395.

Indexed at, Google Scholar , Crossref

12. Cheng (2021) Omega-3 Fatty Acids Supplementation Improve Nutritional Status and Inflammatory Response in Patients With Lung Cancer: A Randomized Clinical Trial. Front nutr 30: 686752.

Indexed at, Google Scholar , Crossref

13. Cheng-Jen and Jin-Ming (2015) Prospective double-blind randomized study on the efficacy and safety of an n-3 fatty acid enriched intravenous fat emulsion in postsurgical gastric and colorectal cancer patients. Nutrition Journal 14: 9.

Indexed at, Google Scholar , Crossref

14. Don and Kaysen (2004) Serum albumin: Relationship to inflammation and nutrition.Seminars in Dialysis 17: 432-437.

Indexed at, Google Scholar , Crossref