Liver Tropism of Carcinoid Tumor Metastasis Driven by Developmental Overlaps Between SI-NECs and Hepatocytes: A Systematic Review Identifying Factors Governing Metastasis and Their Clinical Implications

Objective: This study aims to investigate how overlapping developmental transcription factors and signaling pathways between small intestinal neuroendocrine cells and hepatocytes govern liver-specific metastasis in carcinoid tumors, and to assess the clinical implications of these shared cell-type specific programs for early detection, risk-adapted surveillance, and targeted therapeutic strategies aimed at improving patient outcomes. Background: Small intestinal carcinoid tumors preferentially metastasize to the liver, driving morbidity and mortality, yet traditional explanations like vascular patterns inadequately account for this specificity. Overlapping transcription factors and signaling pathways between SI-NECs and hepatocytes such as FOXA, GATA, SOX, NOTCH, Wnt/β-catenin, Hippo, FGF/HGF, TGF-β, and Dll1/4, may confer “liver-compatible” programs that facilitate adhesion, survival, and proliferation. Understanding these overlaps could enable early detection, targeted surveillance, and therapeutics, redefining organ-specific metastasis mechanisms. Methods: Databases, including PubMed, MEDLINE, Scopus, and Web of Science were searched through March 2026, to investigate overlapping genes/tfs/signaling pathways (FOXA1/2, GATA4/6, SOX4/9, HES1/NOTCH, Wnt/ beta catenin, Hippo/YAP-TAZ, FGF/HGF, TGF-β, and Dll1/4) between SI-NECs and hepatocytes that may have role in governing liver tropism for metastasis of Carcinoid Tumor. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the relevant PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results: Key findings indicate that small intestinal carcinoid tumors exhibit a high propensity for liver metastasis due to overlapping developmental transcription factors and signaling pathways with hepatocytes, including FOXA1/2, GATA4/6, SOX4/9, HES1/NOTCH, Wnt/ beta catenin, Hippo/YAP-TAZ, FGF/HGF, TGF-β, and Dll1/4. These shared programs preserve progenitor-like plasticity, enable responsiveness to hepatic microenvironmental cues, and facilitate adhesion, survival, proliferation, and extracellular matrix remodeling. This compatibility due to overlap explains organ-specific tropism and highlights opportunities for early metastasis detection, risk-adapted surveillance, and targeted therapeutics, providing a framework for understanding liver-directed metastasis in carcinoid tumor patients. Conclusion: Small intestinal carcinoid tumors preferentially metastasize to the liver due to overlapping transcriptional and signaling programs shared with hepatocytes. Factors such as FOXA1/2, GATA4/6, SOX4/9, HES1/NOTCH, Wnt/beta catenin, Hippo/YAP-TAZ, FGF/HGF, TGF-β, and Dll1/4 enable tumor cells to maintain progenitor-like plasticity, respond to hepatic cues, and integrate into the liver microenvironment. The high propensity of small intestinal carcinoid tumors to metastasize to the liver can be explained by overlaps in transcription factors, signaling pathways, and progenitor-like features between SI-NECs and hepatocytes. This creates a microenvironment and functional compatibility, making the liver a preferential metastatic site.