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Gene & Protein in Disease Pre-metastatic niche oral cancer: Insights

1. Introduction the association between poor survival rate and lymph node
metastasis in oral cancer patients. 14,18 In this study, we
Metastasis involves the spread of cancer cells from the performed a bioinformatic analysis to identify differentially
primary tumor site to surrounding tissues and distant expressed genes (DEGs) and pathways associated with the
organs. Neoplastic cells circulating in the blood are pre-metastatic niche and perineural invasion in OSCC.
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often likened to metastatic “seeds” that have the ability to
fertilize a microenvironmental “soil” of organs secondary 2. Methods
to the tumor. However, reaching another site in the
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body does not guarantee the formation of a metastatic 2.1. Data retrieval and processing
tumor, where successful invasion and proliferation of The Gene Expression Omnibus (GEO) database (www.
neoplastic cells depends on their interaction with the local ncbi.nlm.nih.gov/geo) is one of the leading platforms
microenvironment. Primary tumor cells are capable of for the storage and distribution of gene expression data
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modifying a microenvironment distant from the primary generated through microarray technology, accessible
tumor locus before the arrival of metastatic cells, creating through a free, public web interface. We evaluated GEO
what is known as the pre-metastatic niche. 4 datasets with metastatic and non-metastatic primary
A pre-requisite for metastasis spread is the ability of these tumor samples (GSE2280), healthy oral tissues and OSCC
cells to exit the bloodstream, peripheral nerves, and lymphatic samples (GSE31056), and metastatic lymph nodes from
vessels, reach the stroma, and exhibit a pre-dilection to patients with OSCC and normal lymph node samples
lodge in specific organs. The local microenvironment, (GSE70604). GEO2R was applied to screen mRNAs
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characterized by early changes that dictate the pattern of differentially expressed between tissues exhibiting features
metastatic spread, is referred to as the “pre-metastatic niche.” of a pre-metastatic niche and normal tissue samples.
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Mechanical forces within vascular channels govern the 2.2. RNA-seq and clinical information data from The
initial dispersion of cells originating from primary tumors Cancer Genome Atlas
to distant sites. The attachment, extravasation, survival, and
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proliferation of neoplastic cells are important for metastatic The Cancer Genome Atlas (TCGA) analyses were
growth. In response to cytokines such as vascular endothelial performed as previously described. The selected cancer
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growth factor receptors and matrix metalloproteinases subtypes included non-metastatic and metastatic OSCC
(MMPs), tumor-associated cells, such as hematopoietic samples. We also performed an analysis of perineural
progenitor cells and macrophages, modify the distant sites, invasion-negative and perineural invasion-positive tumor
allowing cancer cell adhesion, invasion, and growth. 4 samples. Co-expressed upregulated and downregulated
DEGs from the gene expression profiles were combined and
Neoplastic cells can reach secondary sites through
nerves found in the peripheral nervous system, a process identified using Venn Diagram 2.1.0 (http://bioinfogp.cnb.
called perineural invasion. 7,9,10 The mechanism underlying csic.es/tools/venny/index.html). A significance threshold
perineural invasion is not well understood. Cancer cells of adjusted P < 0.05 and a log of fold change (logFC) ≥ 1
must acquire mechanisms that enable their survival outside was set as the cut-off criterion.
the primary environment, facilitating communication with 2.3. Functional enrichment analysis
the nerve microenvironment in several tumors, including
oral squamous cell carcinoma (OSCC). 11,12 We performed gene list collection and functional
enrichment analysis as previously described. The data
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OSCC is a malignant neoplasia that can affect different of associated genes and pathways for Kyoto Encyclopedia
regions of the oral cavity. The main risk factors include of Genes and Genomes (KEGG) analyses are available on
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substances such as tobacco and alcohol, chronic lesions, the Database for Annotation, Visualization, and Integrated
human papillomavirus (HPV) infection, and ultraviolet Discovery (DAVID) platform (https://david.ncifcrf.gov/),
radiation. 5,13-16 These pathological factors influence which acts as a data warehouse whose central objective is to
several metabolic processes, disrupt cellular homeostasis, extract meaningful biological information such as functions
and induce genomic changes, which can promote and pathways of genes and proteins. KEGG analyses were
carcinogenesis in the long run. 17-19 performed using the DAVID platform to annotate DEG
Globally, approximately 20 million new cancer cases functions and evaluate their pathway enrichment.
are reported annually, with nearly 10 million cancer-
related deaths. The majority of cancer-related deaths are 2.4. Oral cancer expression analyses
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due to metastasis. In patients with oral cancer, metastasis Additional web resources were used as sources of
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development is well characterized, and studies have shown information and analytical tools for head and neck cancer

Volume 3 Issue 4 (2024) 2 doi: 10.36922/gpd.2971