Nian H, Bai Y, Wang HY, Yu H, Zhang ZL, Shi RH, Zhang S, Wu YB, Zhou DH, Du QC. Targeting the Osteopontin-regulated PI3K/AKT signaling pathway: A molecular approach to overcome drug resistance and metastasis in gastrointestinal tumors. World J Gastrointest Oncol 2025; 17(11): 109923 [PMID: 41281471 DOI: 10.4251/wjgo.v17.i11.109923]
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November 23, 2025, 13:45
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Reader Comments:
The review by Nian et al. offers a thorough and thoughtfully articulated overview of current insights into Osteopontin (OPN)–mediated PI3K/AKT signaling and its pivotal influence on gastrointestinal cancer progression, metastatic behavior, and therapeutic resistance. The authors skillfully synthesize mechanistic and translational findings, underscoring how OPN-driven activation of the PI3K/AKT pathway promotes epithelial–mesenchymal transition, metabolic adaptation, immune escape, and chemoresistance. Their discussion of OPN splice variants, tumor microenvironment interactions, and biomarker-informed therapeutic strategies provides meaningful guidance for advancing precision oncology.
A major strength of the review is its emphasis on the inherent complexity and compensatory nature of OPN–PI3K/AKT signaling, which helps explain the challenges associated with single-agent therapeutic approaches. The recommendation to pursue combination strategies—such as pairing PI3K/AKT inhibitors with immune checkpoint blockade or OPN-targeted antibodies—is timely and supported by accumulating preclinical data. Furthermore, the manuscript’s focus on PIK3CA mutation subsets and OPN expression as potential predictive biomarkers may enable more refined patient stratification in future clinical trials.
Despite these promising avenues, clinical translation remains constrained. Current trials evaluating PI3K/AKT inhibitors in gastrointestinal malignancies have yielded limited efficacy and notable toxicity, highlighting the need for more rigorous biomarker-driven study designs. Although the review acknowledges these issues, a deeper appraisal of the reasons underlying clinical shortcomings—and the specific contribution of OPN signaling to these obstacles—would further strengthen its clinical impact.
In sum, this review provides a valuable contribution by elucidating the diverse oncogenic roles of OPN and outlining strategic paths toward overcoming therapeutic resistance. Continued research into isoform-specific activity, tumor microenvironmental dynamics, and rational combinatorial regimens will be crucial for realizing the therapeutic potential of targeting the OPN–PI3K/AKT axis in gastrointestinal cancers.
Reader's ID:
04731896
Submitted on:
November 23, 2025, 08:50
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Reader Comment Standards for Published Articles:
1 Title
Does the title reflect the main subject/hypothesis of the manuscript?
2 Abstract
Does the abstract summarize and reflect the work described in the manuscript?
3 Key Words
Do the key words reflect the focus of the manuscript?
4 Background
Does the manuscript adequately describe the background, present status and significance of the study?
5 Methods
Does the manuscript describe methods (e.g., experiments, data analysis, surveys, and clinical trials, etc.) in adequate detail?
6 Results
Are the research objectives achieved by the experiments used in this study?
Has the study made meaningful contributions towards research progress in this field?
7 Discussion
Does the manuscript interpret the findings adequately and appropriately, highlighting the key points concisely, clearly and logically?
Are the findings and their applicability/relevance to the literature stated in a clear and definite manner?
Is the Discussion accurate and does it discuss the paper’s scientific significance and/or relevance to clinical practice sufficiently?
8 Illustrations and Tables
Are the figures, diagrams and tables sufficient, good quality and appropriately illustrative of the paper contents?
Do figures require labeling with arrows, asterisks, etc., or better legends?
9 Biostatistics
Does the manuscript meet the requirements of biostatistics?
10 Units
Does the manuscript meet the requirements of use of SI units?
11 References
Does the manuscript appropriately cite the latest, important and authoritative references in the Introduction and Discussion sections?
Does the author self-cite, omit, incorrectly cite and/or over-cite references?
12 Quality of manuscript organization and presentation
Is the manuscript concisely and coherently organized and presented?
Are the style, language and grammar accurate and appropriate?
13 Ethics statements
For all manuscripts involving human studies and/or animal experiments, author(s) must submit the related formal ethics documents that were reviewed and approved by their local ethical review committee. Did the manuscript meet the requirements of ethics?
Scientific Quality:
The overall quality of the manuscript, based on the above-listed criteria, should be evaluated and classified according to the following five categories
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Reader Comments:
This minireview describes the important role of 0steopontin (OPN)-regulated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in gastrointestinal tumor proliferation, metastasis, chemoresistance, and immune evasion.
Targeting osteopontin-regulated PI3K/AKT signaling pathway with PI3K/AKT inhibitors or OPN neutralizing antibodies may reverse drug resistance and suppress metastasis. Further research should be needed to find combination therapies which have the potential to provide more effective anti-tumor activity towards refractory cancers.