Page 259 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Metastasis gene expression in colorectal cancer

arises from adenomatous polyps through the adenoma- disease’s heterogeneity and clinical outcomes. Beyond
7
carcinoma sequence (ACS), characterized by genetic the classical ACS and the role of epithelial-mesenchymal
mutations that lead to uncontrolled cell growth. This transition (EMT) regulators, recent research has
6,7
development shows the importance of early detection and illuminated several additional mechanisms that underpin
screening strategies in reducing CRC-related mortality. 7-9 CRC advancement and metastatic spread. One critical
7
aspect is the dysregulation of multiple cellular signaling
In addition to genetic and epigenetic alterations,
metabolic reprogramming has emerged as a hallmark pathways, which orchestrate the malignant transformation
and dissemination of CRC cells. Notably, the Wnt/β-
of CRC progression. Cancer cells frequently undergo catenin pathway is frequently activated in CRC, driving
metabolic shifts to meet the increased energy demands uncontrolled proliferation and survival of tumor cells.
20
and biosynthetic needs associated with rapid proliferation Mutations in key genes can disrupt cellular homeostasis,
and metastasis. For instance, enhanced glycolysis, thereby facilitating the accumulation of genetic changes
10
known as the Warburg effect, supports tumor growth that drive tumorigenesis. Snail family transcriptional
10
even in the presence of oxygen. Moreover, alterations repressor 1 (SNAI1), zinc finger e-box binding homeobox
in lipid metabolism and amino acid utilization have 1 (ZEB1), Slug, Twist, metastasis-associated protein 3
been implicated in CRC aggressiveness. These metabolic (MTA3), as transcription factors, and tumor necrosis
adaptations not only sustain tumor cell survival but also factor-alpha (TNF-α), a pro-inflammatory cytokine
modulate the immune microenvironment, influencing the signaling are also shown to be involved in CRC progression
recruitment and function of immune cells such as tumor- and metastasis. 21-23 In particular, SNAI1, Slug, and MTA3
associated macrophages and myeloid-derived suppressor are pivotal regulators of EMT, a process that enables cancer
cells. Therapeutic strategies targeting metabolic cells to acquire migratory properties. They are also members
11
vulnerabilities of CRC cells hold promise for disrupting of the metastasis-associated protein family. 24,25 TNF-α has
tumor progression and overcoming resistance to existing been shown to induce EMT in CRC cells by stabilizing
treatments. SNAI1 through the AKT/GSK-3β signaling pathway.
26
Chronic conditions and external stressors can This pathway enhances SNAI1’s nuclear localization and
significantly influence the metastasis of CRC, often leading promotes the switch from E-cadherin to N-cadherin
21
to considerable morbidity and mortality. The metastatic expression, a hallmark of EMT. Meanwhile, ZEB1 and
process is influenced by various factors, including chronic Twist also contribute to this process by responding to
inflammation, which can be exacerbated by conditions various microenvironmental signals and facilitating the
27
such as chronic hepatitis B (CHB) and psychological transition of epithelial cells into mesenchymal-like cells.
stress. 12,13 Paradoxically, CHB may also protect against The interplay between these factors not only drives tumor
colorectal liver metastasis due to its sclerosing effect on invasion but also correlates with unfavorable clinical
the liver and certain immune-mediated mechanisms. outcomes in CRC patients, underscoring their potential as
14
Psychological stress and a perturbed gut microbiome targets for therapy in managing cancer metastasis.
can promote CRC growth and metastasis. Single- Clinically, advancements in molecular profiling have
15
cell RNA sequencing has revealed that chronic stress enabled the stratification of CRC patients based on genetic
can induce an immunosuppressive environment that and epigenetic signatures, allowing for more personalized
encourages CRC metastasis. Studies have shown that therapeutic approaches. Biomarkers such as SNAI1, ZEB1,
16
chronic inflammation can activate oncogenic pathways, Slug, Twist, MTA3, and TNF-α are increasingly used
promoting tumor growth and metastasis. Furthermore, to guide treatment decisions, particularly regarding the
17
the tumor microenvironment plays an important role in selection of targeted agents and immunotherapies. Immune
the progression of CRC, with immune cells like tumor- checkpoint inhibitors have shown remarkable efficacy in a
associated macrophages recruited to support metastatic subset of CRC patients with high expression, highlighting
spread. Research indicates that chronic stress can alter the potential of immunotherapeutic approaches in against
18
the gut microbiome, further enhancing the metastatic this disease. 28,29 However, resistance mechanisms and the
potential of CRC. Understanding these mechanisms is limited response in tumor microenvironment remain
19
vital for developing targeted therapies, such as inhibition challenges that necessitate further investigation. The
of related genes in CRC, aimed at preventing or reducing interplay of these pathways not only promotes tumor
metastasis in patients with chronic CRC. growth but also provides potential therapeutic targets for
CRC progression and metastasis are governed intervention.
by a complex interplay of genetic, epigenetic, and In summary, the progression and metastasis of CRC
microenvironmental factors, each contributing to the are driven by a complex interplay of genetic mutations,

Volume 9 Issue 3 (2025) 251 doi: 10.36922/EJMO025210202