Exploring the role of formin-like genes in gastric cancer progression, prognosis, and their potential as therapeutic targets
Gastric cancer remains a formidable global health challenge, ranking as the fifth most common cancer worldwide and the third most common cause of cancer death 3 . Despite advances in treatment, the prognosis for advanced gastric cancer remains poor, primarily due to the cancer's ability to evade detection and treatment until its later stages.
The search for better understanding and new therapeutic targets has led scientists to investigate the very architectural components of cancer cells—the cytoskeleton. Enter the formin-like gene family (FMNLs), a group of molecules now emerging as crucial regulators in gastric cancer's development and progression.
These molecular architects, long known for their role in building the cellular skeleton, are now taking center stage in cancer research. Recent breakthroughs have revealed that these proteins not only shape cancer cells but may also influence how the immune system responds to tumors. This article explores the fascinating discovery of how formin-like genes contribute to gastric cancer and why they represent promising new targets for diagnosis and treatment.
5th most common cancer worldwide
3rd leading cause of cancer deaths
Formin genes as key regulators
To understand why formins are so important in cancer, we must first appreciate their normal function in cells. Formins are highly conserved proteins that act as master regulators of the actin cytoskeleton—the intricate network of protein filaments that gives cells their shape, enables movement, and facilitates division 3 5 .
Think of formins as construction foremen at a building site, directing where and how the structural framework should be assembled.
The formin family is characterized by distinctive structural domains, particularly the FH2 (Formin Homology 2) domain, which is responsible for nucleating and elongating actin filaments 4 .
This domain works in concert with the FH1 domain, which helps recruit actin-building blocks to the growing filament. Through these specialized domains, formins govern essential cellular processes including cell division, adhesion, and migration—all capabilities that cancer cells co-opt for their destructive purposes.
In the context of cancer, when formins become dysregulated, they can transform from orderly construction foremen into chaotic directors of invasion and metastasis. They help cancer cells reshape themselves, break away from their original locations, and invade new territories—the deadly process of metastasis that makes cancer so difficult to treat.
Groundbreaking research published in 2020 provided the first comprehensive analysis of the formin-like gene family in gastric cancer 1 . Through sophisticated bioinformatics analysis of large clinical datasets, scientists systematically characterized the expression patterns and clinical significance of three key family members: FMNL1, FMNL2, and FMNL3.
Significantly upregulated in gastric cancer
Significantly upregulated in gastric cancer
Significantly upregulated in gastric cancer
| Gene | Expression in Gastric Cancer | Association with Cancer Stage | Prognostic Value |
|---|---|---|---|
| FMNL1 | Significantly upregulated | Higher in advanced stages | Poor overall survival |
| FMNL2 | Significantly upregulated | Higher in advanced stages | Not independently significant |
| FMNL3 | Significantly upregulated | Higher in advanced stages | Poor overall survival |
Perhaps the most surprising discovery came from analyzing the relationship between FMNLs and the immune environment within tumors. The researchers found that FMNL expressions significantly correlated with immune cell infiltration in gastric cancer 1 . This finding suggested that these molecules might not only shape cancer cells themselves but also influence how immune cells interact with the tumor—a double-edged sword that makes them particularly interesting therapeutic targets.
While the systematic characterization of FMNL mRNA expression provided crucial insights, it left an important question unanswered: how do these findings translate to the actual protein level in human tumors? A dedicated team of researchers tackled this question head-on in a detailed study published in 2021, focusing on two formin proteins: FHOD1 and FMNL1 3 5 .
The investigation began with analysis of existing cancer databases, which confirmed that high FHOD1 and FMNL1 mRNA expression correlated with reduced overall survival in intestinal-type gastric cancer patients 5 .
The team examined formin expression and localization in multiple gastric cancer cell lines (AGS, MKN28, MKN45) using sophisticated techniques including western blotting and immunofluorescence 5 .
The core of the study involved analyzing tissue microarrays from 190 patients with intestinal-type gastric adenocarcinomas. These arrays included multiple tissue samples from each patient, taken from both the central tumor area and the invasive front 5 .
Researchers used specialized antibodies against FHOD1 and FMNL1 to detect these proteins in tissue samples, employing a staining technique that allowed precise visualization of protein presence and distribution 5 .
A crucial aspect of the methodology involved correlating formin protein expression with the presence of tumor-infiltrating T lymphocytes, specifically CD8+ cells, which are known to play critical roles in anti-tumor immunity 5 .
Both FHOD1 and FMNL1 proteins showed cytoplasmic expression along actin filaments in gastric cancer cells, consistent with their known roles in cytoskeletal regulation 5 .
Elevated FMNL1 was associated with larger tumor size and higher disease stage 5 . This finding provided a potential explanation for how formins contribute to cancer progression.
Perhaps the most intriguing result came from the immune correlation analysis. The researchers discovered that tumor cell FHOD1 expression strongly correlated with high numbers of tumor-infiltrating CD8+ T lymphocytes 5 . This relationship suggested a previously unappreciated connection between cancer cell architecture and immune recognition.
| Parameter | FHOD1 | FMNL1 |
|---|---|---|
| Cellular Localization | Cytoplasmic, along actin filaments | Cytoplasmic, along actin filaments |
| Association with Clinical Features | Downregulated in TP53-mutated tumors | Associated with larger tumor size and higher disease stage |
| Immune Correlation | Strong correlation with CD8+ T lymphocyte infiltration | Not specifically reported |
| Prognostic Significance | No direct correlation with survival in this cohort | No direct correlation with survival in this cohort |
Studying formins in cancer requires a specialized set of research tools and techniques. The methodologies developed and utilized in the studies we've examined provide a comprehensive toolkit for exploring these fascinating proteins.
Oncomine, UALCAN, Kaplan-Meier Plotter, TIMER, LinkedOmics 1
Application: Analyzing FMNL expression patterns, survival correlations, and immune associations
| Research Tool | Specific Examples | Application in Formin Research |
|---|---|---|
| Bioinformatics Databases | Oncomine, UALCAN, Kaplan-Meier Plotter, TIMER, LinkedOmics 1 | Analyzing FMNL expression patterns, survival correlations, and immune associations |
| Gene Expression Analysis | RNA-sequencing, Quantitative RT-PCR 6 7 | Measuring FMNL mRNA levels in cancer vs. normal tissues |
| Protein Detection | Western blotting, Immunofluorescence, Immunohistochemistry 3 5 6 | Detecting and localizing formin proteins in cells and tissues |
| Cell Culture Models | Gastric cancer cell lines (AGS, MKN28, MKN45, HGC-27) 5 6 7 | Studying formin function in controlled laboratory settings |
| Genetic Manipulation | Short hairpin RNA (shRNA), Lentiviral overexpression vectors 6 7 | Knocking down or overexpressing formins to study their functional roles |
| Tissue Specimens | Tumor microarrays (TMAs), Patient-derived tissue sections 3 5 | Validating findings in clinically relevant human samples |
| Functional Assays | MTT assays, Wound healing, Transwell invasion, Flow cytometry 7 | Assessing how formins affect cancer cell behaviors |
This comprehensive toolkit enables researchers to move from computational predictions to functional validation, creating a complete picture of how formins contribute to gastric cancer progression. Each method provides a different piece of the puzzle, from large-scale pattern analysis to detailed mechanistic studies.
The journey into understanding formins in gastric cancer reveals a fascinating story of how basic cellular machinery can be co-opted in disease states. The systematic characterization of the formin-like gene family has uncovered their roles as both cellular architects and potential immune modulators in gastric cancer.
Formins function as both cellular architects and immune modulators
Potential to serve as novel biomarkers for disease progression
Promising targets for novel cancer therapies
Perhaps most promising is the emerging understanding that formins sit at the intersection of cancer cell biology and tumor immunology. The discovery that FHOD1 expression correlates with CD8+ T lymphocyte infiltration 5 suggests that these molecules might help shape not just cancer cells themselves, but also the immune environment surrounding the tumor. This dual role makes them particularly attractive as potential therapeutic targets.
As research continues, formins may serve as novel prognostic biomarkers that help clinicians identify patients with more aggressive disease, potentially guiding treatment decisions. Beyond prognosis, the functional importance of formins in cancer cell invasion and migration positions them as potential targets for novel therapies that could slow or prevent metastasis—the deadliest aspect of gastric cancer.
While many questions remain, the systematic investigation of formins in gastric cancer represents an excellent example of how basic cell biology can illuminate clinical challenges, offering new hope for understanding and ultimately conquering this devastating disease. As research progresses, we may find that targeting these cellular architects provides a powerful new approach to controlling gastric cancer's growth and spread.
References will be listed here in the final version.