Cancer Stem Cells in Human Gastrointestinal and Hepatic Cancers

Abstract

Gastrointestinal cancers, including gastric, hepatic, and colorectal cancers, represent a major public health problem globally. Although the 5-year survival rate of gastrointestinal tumors has been greatly improved due to the progress of diagnostic and therapeutic strategies, therapeutic resistance and distant metastasis remain the leading causes of cancer-related death in patients with gastrointestinal tumors. Cancer stem cells (CSCs) are a population of self-renewal cells with extremely strong carcinogenic potency, contributing to the progression, metastasis, and therapeutic resistance of gastrointestinal tumors. It is generally accepted that gastrointestinal CSCs have the characteristics of self-renewal, pluripotency, tumorigenicity, metastatic potential, and therapeutic resistance. Hence, understanding the behaviors of gastrointestinal CSCs is important for characterizing the stemness landscapes of gastrointestinal tumors and developing promising strategies for the treatment of gastrointestinal tumors. This review aims to discuss the basic characteristics of gastrointestinal CSCs, existing approaches to define and isolate CSCs, and canonical molecular pathways involved in the regulation of gastrointestinal CSCs. More importantly, potential strategies targeting gastrointestinal CSCs are proposed to overcome the limitations of current therapies.

Keywords

cancer stem cells / gastrointestinal cancer / hepatic cancer / stemness / therapeutic strategy

References

[1] R. Siegel, T. B. Kratzer, A. N. Giaquinto, H. Sung, and A. Jemal, “Cancer Statistics, 2025,” CA: A Cancer Journal for Clinicians 75, no. 1 (2025): 10–45.

[2] S. Zeki, T. Graham, and N. Wright, “Stem Cells and Their Implications for Colorectal Cancer,” Nature Reviews Gastroenterology & Hepatology 8, no. 2 (2011): 90–100.

[3] A. Zeuner, M. Todaro, G. Stassi, and R. De Maria, “Colorectal Cancer Stem Cells: From the Crypt to the Clinic,” Cell Stem Cell 15, no. 6 (2014): 692–705.

[4] B. Boman and E. Huang, “Human Colon Cancer Stem Cells: A New Paradigm in Gastrointestinal Oncology,” Journal of Clinical Oncology 26, no. 17 (2008): 2828–2838.

[5] E. Batlle and H. Clevers, “Cancer Stem Cells Revisited,” Nature Medicine 23, no. 10 (2017): 1124–1134.

[6] P. Dalerba, S. J. Dylla, I. Park, et al., “Phenotypic Characterization of human Colorectal Cancer Stem Cells,” PNAS 104, no. 24 (2007): 10158–10163.

[7] M. Todaro, M. G. Francipane, J. P. Medema, and G. Stassi, “Colon Cancer Stem Cells: Promise of Targeted Therapy,” Gastroenterology 138, no. 6 (2010): 2151–2162.

[8] H. Wang, P. Gong, T. Chen, et al., “Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single-Cell Analysis of Transcriptome and Telomeres,” Advanced Science (Weinheim) 8, no. 8 (2021): 2004320.

[9] E. Huang and M. Wicha, “Colon Cancer Stem Cells: Implications for Prevention and Therapy,” Trends in Molecular Medicine 14, no. 11 (2008): 503–509.

[10] W. H. Fridman, I. Miller, C. Sautès-Fridman, and A. T. Byrne, “Therapeutic Targeting of the Colorectal Tumor Stroma,” Gastroenterology 158, no. 2 (2020): 303–321.

[11] L. Vermeulen and H. Snippert, “Stem Cell Dynamics in Homeostasis and Cancer of the Intestine,” Nature Reviews Cancer 14, no. 7 (2014): 468–480.

[12] H. Wang, G. Cui, B. Yu, M. Sun, and H. Yang, “Cancer Stem Cell Niche in Colorectal Cancer and Targeted Therapies,” Current Pharmaceutical Design 26, no. 17 (2020): 1979–1993.

[13] L. Ricci-Vitiani, D. G. Lombardi, E. Pilozzi, et al., “Identification and Expansion of human Colon-cancer-initiating Cells,” Nature 445, no. 7123 (2007): 111–115.

[14] S. K. Singh, C. Hawkins, I. D. Clarke, et al., “Identification of human Brain Tumour Initiating Cells,” Nature 432, no. 7015 (2004): 396–401.

[15] M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke, “Prospective Identification of Tumorigenic Breast Cancer Cells,” PNAS 100, no. 7 (2003): 3983–3988.

[16] A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J. Maitland, “Prospective Identification of Tumorigenic Prostate Cancer Stem Cells,” Cancer Research 65, no. 23 (2005): 10946–10951.

[17] C. F. B. Kim, E. L. Jackson, A. E. Woolfenden, et al., “Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer,” Cell 121, no. 6 (2005): 823–835.

[18] C. A. O'Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A human Colon Cancer Cell Capable of Initiating Tumour Growth in Immunodeficient Mice,” Nature 445, no. 7123 (2007): 106–110.

[19] Z. F. Yang, D. W. Ho, M. N. Ng, et al., “Significance of CD90+ Cancer Stem Cells in human Liver Cancer,” Cancer Cell 13, no. 2 (2008): 153–166.

[20] M. J. Son, K. Woolard, D. Nam, J. Lee, and H. A. Fine, “SSEA-1 Is an Enrichment Marker for Tumor-initiating Cells in human Glioblastoma,” Cell Stem Cell 4, no. 5 (2009): 440–452.

[21] C. Li, D. G. Heidt, P. Dalerba, et al., “Identification of Pancreatic Cancer Stem Cells,” Cancer Research 67, no. 3 (2007): 1030–1037.

[22] T. Schatton, G. F. Murphy, N. Y. Frank, et al., “Identification of Cells Initiating human Melanomas,” Nature 451, no. 7176 (2008): 345–349.

[23] L. van der Flier and H. Clevers, “Stem Cells, Self-renewal, and Differentiation in the Intestinal Epithelium,” Annual Review of Physiology 71 (2009): 241–260.

[24] D. Bakhshinyan, A. A. Adile, M. A. Qazi, et al., “Introduction to Cancer Stem Cells: Past, Present, and Future,” Methods in Molecular Biology 1692 (2018): 1–16.

[25] U. Mala, T. Baral, and K. Somasundaram, “Integrative Analysis of Cell Adhesion Molecules in Glioblastoma Identified Prostaglandin F2 Receptor Inhibitor (PTGFRN) as an Essential Gene,” BMC Cancer 22, no. 1 (2022): 642.

[26] L. M. Rota, D. A. Lazzarino, A. N. Ziegler, D. LeRoith, and T. L. Wood, “Determining Mammosphere-forming Potential: Application of the Limiting Dilution Analysis,” Journal of Mammary Gland Biology and Neoplasia 17, no. 2 (2012): 119–123.

[27] L. Walcher, A. Kistenmacher, H. Suo, et al., “Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies,” Frontiers in Immunology 11 (2020): 1280.

[28] J. K. Choi, I. Kwak, S. Yoon, H. Cho, and B. Moon, “A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer,” Biomedicines 10, no. 4 (2022): 859.

[29] A. Kreso and J. Dick, “Evolution of the Cancer Stem Cell Model,” Cell Stem Cell 14, no. 3 (2014): 275–291.

[30] E. Vlashi and F. Pajonk, “Cancer Stem Cells, Cancer Cell Plasticity and Radiation Therapy,” Seminars in Cancer Biology 31 (2015): 28–35.

[31] A. Hamburger and S. Salmon, “Primary Bioassay of human Tumor Stem Cells,” Science 197, no. 4302 (1977): 461–463.

[32] D. Bonnet and J. Dick, “Human Acute Myeloid Leukemia Is Organized as a Hierarchy That Originates From a Primitive Hematopoietic Cell,” Nature Medicine 3, no. 7 (1997): 730–737.

[33] T. Ishiwata, Y. Matsuda, H. Yoshimura, et al., “Pancreatic Cancer Stem Cells: Features and Detection Methods,” Pathology Oncology Research 24, no. 4 (2018): 797–805.

[34] P. Xia and D. Liu, “Cancer Stem Cell Markers for Liver Cancer and Pancreatic Cancer,” Stem Cell Research 60 (2022): 102701.

[35] S. Kohno, S. Kitajima, N. Sasaki, and C. Takahashi, “Retinoblastoma Tumor Suppressor Functions Shared by Stem Cell and Cancer Cell Strategies,” World Journal of Stem Cells 8, no. 4 (2016): 170–184.

[36] C. Ginestier, M. H. Hur, E. Charafe-Jauffret, et al., “ALDH1 is a Marker of Normal and Malignant human Mammary Stem Cells and a Predictor of Poor Clinical Outcome,” Cell Stem Cell 1, no. 5 (2007): 555–567.

[37] J. Bu, Y. Zhang, S. Wu, et al., “KK-LC-1 as a Therapeutic Target to Eliminate ALDH(+) Stem Cells in Triple Negative Breast Cancer,” Nature Communications 14, no. 1 (2023): 2602.

[38] H. Wang, Y. Mei, C. Luo, et al., “Single-Cell Analyses Reveal Mechanisms of Cancer Stem Cell Maintenance and Epithelial-Mesenchymal Transition in Recurrent Bladder Cancer,” Clinical Cancer Research 27, no. 22 (2021): 6265–6278.

[39] Y. Al Salhi, M. B. Sequi, F. M. Valenzi, et al., “Cancer Stem Cells and Prostate Cancer: A Narrative Review,” International Journal of Molecular Sciences 24, no. 9 (2023): 7746.

[40] J. Deng, T. Pan, C. Lv, et al., “Exosomal Transfer Leads to Chemoresistance Through Oxidative Phosphorylation-mediated Stemness Phenotype in Colorectal Cancer,” Theranostics 13, no. 14 (2023): 5057–5074.

[41] L. Du, H. Wang, L. He, et al., “CD44 is of Functional Importance for Colorectal Cancer Stem Cells,” Clinical Cancer Research 14, no. 21 (2008): 6751–6760.

[42] S. Liu, H. Zhao, Y. Hu, et al., “Lactate Promotes Metastasis of Normoxic Colorectal Cancer Stem Cells Through PGC-1alpha-mediated Oxidative Phosphorylation,” Cell Death & Disease 13, no. 7 (2022): 651.

[43] W. Zhao, S. Dai, L. Yue, et al., “Emerging Mechanisms Progress of Colorectal Cancer Liver Metastasis,” Frontiers in Endocrinology (Lausanne) 13 (2022): 1081585.

[44] B. Huang, H. Yang, X. Cheng, et al., “tRF/miR-1280 Suppresses Stem Cell-Like Cells and Metastasis in Colorectal Cancer,” Cancer Research 77, no. 12 (2017): 3194–3206.

[45] D. Wang, L. Fu, H. Sun, L. Guo, and R. N. DuBois, “Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice,” Gastroenterology 149, no. 7 (2015): 1884–1895. e4.

[46] F. de Sousa e Melo, A. V. Kurtova, J. M. Harnoss, et al., “A Distinct Role for Lgr5(+) Stem Cells in Primary and Metastatic Colon Cancer,” Nature 543, no. 7647 (2017): 676–680.

[47] R. Li, X. Liu, X. Huang, et al., “Single-cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-specific Metastasis,” Gut 73, no. 3 (2024): 470–484.

[48] K. Ganesh, H. Basnet, Y. Kaygusuz, et al., “L1CAM defines the Regenerative Origin of Metastasis-initiating Cells in Colorectal Cancer,” Nature Cancer 1, no. 1 (2020): 28–45.

[49] P. Chandrakesan, N. Weygant, R. May, et al., “DCLK1 facilitates Intestinal Tumor Growth via Enhancing Pluripotency and Epithelial Mesenchymal Transition,” Oncotarget 5, no. 19 (2014): 9269–9280.

[50] Y. Zhan, D. Sun, J. Gao, et al., “Single-cell Transcriptomics Reveals Intratumor Heterogeneity and the Potential Roles of Cancer Stem Cells and myCAFs in Colorectal Cancer Liver Metastasis and Recurrence,” Cancer Letters 612 (2025): 217452.

[51] Y. Huang, B. Zhou, H. Luo, et al., “ZnAs@SiO(2) Nanoparticles as a Potential Anti-tumor Drug for Targeting Stemness and Epithelial-mesenchymal Transition in Hepatocellular Carcinoma via SHP-1/JAK2/STAT3 Signaling,” Theranostics 9, no. 15 (2019): 4391–4408.

[52] Z. Chen, L. Xiang, L. Li, et al., “TGF-β1 Induced Deficiency of linc00261 Promotes Epithelial-mesenchymal-transition and Stemness of Hepatocellular Carcinoma via Modulating SMAD3,” Journal of Translational Medicine 20, no. 1 (2022): 75.

[53] H. Huan, D. Yang, X. Wen, et al., “HOXB7 accelerates the Malignant Progression of Hepatocellular Carcinoma by Promoting Stemness and Epithelial-mesenchymal Transition,” Journal of Experimental & Clinical Cancer Research 36, no. 1 (2017): 86.

[54] J. Zhou, Q. Zeng, H. Wang, et al., “MicroRNA-125b Attenuates Epithelial-mesenchymal Transitions and Targets Stem-Like Liver Cancer Cells Through Small Mothers Against Decapentaplegic 2 and 4,” Hepatology 62, no. 3 (2015): 801–815.

[55] H. Ou, Z. Chen, L. Xiang, et al., “Frizzled 2-induced Epithelial-mesenchymal Transition Correlates With Vasculogenic Mimicry, Stemness, and Hippo Signaling in Hepatocellular Carcinoma,” Cancer Science 110, no. 4 (2019): 1169–1182.

[56] S. W. Fung, P. F. Cheung, C. W. Yip, et al., “The ATP-binding Cassette Transporter ABCF1 Is a Hepatic Oncofetal Protein That Promotes Chemoresistance, EMT and Cancer Stemness in Hepatocellular Carcinoma,” Cancer Letters 457 (2019): 98–109.

[57] S. Modi and V. Kulkarni, “Discovery of VEGFR-2 Inhibitors Exerting Significant Anticancer Activity Against CD44+ and CD133+ Cancer Stem Cells (CSCs): Reversal of TGF-β Induced Epithelial-mesenchymal Transition (EMT) in Hepatocellular Carcinoma,” European Journal of Medicinal Chemistry 207 (2020): 112851.

[58] Q. Fan, Y. Jing, G. Yu, et al., “Tumor-associated Macrophages Promote Cancer Stem Cell-Like Properties via Transforming Growth Factor-beta1-induced Epithelial-mesenchymal Transition in Hepatocellular Carcinoma,” Cancer Letters 352, no. 2 (2014): 160–168.

[59] L. Jing, Z. Ruan, H. Sun, et al., “Epithelial-mesenchymal Transition Induced Cancer-stem-cell-Like Characteristics in Hepatocellular Carcinoma,” Journal of Cellular Physiology 234, no. 10 (2019): 18448–18458.

[60] J. E. Choi, J. S. Bae, M. J. Kang, et al., “Expression of Epithelial-mesenchymal Transition and Cancer Stem Cell Markers in Colorectal Adenocarcinoma: Clinicopathological Significance,” Oncology Reports 38, no. 3 (2017): 1695–1705.

[61] J. Jiang, F. Ye, X. Yang, et al., “Peri-tumor Associated Fibroblasts Promote Intrahepatic Metastasis of Hepatocellular Carcinoma by Recruiting Cancer Stem Cells,” Cancer Letters 404 (2017): 19–28.

[62] I. Gasmi, C. Machou, A. Rodrigues, et al., “Interleukin-17 Programs Liver Progenitor Cell Transformation Into Cancer Stem Cells Through miR-122 Downregulation With Increased Risk of Primary Liver Cancer Initiation,” International Journal of Biological Sciences 18, no. 5 (2022): 1944–1960.

[63] F. Lai, W. Liu, Y. Jing, et al., “Lipopolysaccharide Supports Maintaining the Stemness of CD133(+) Hepatoma Cells Through Activation of the NF-κB/HIF-1α Pathway,” Cancer Letters 378, no. 2 (2016): 131–141.

[64] S. Wan, E. Zhao, I. Kryczek, et al., “Tumor-associated Macrophages Produce Interleukin 6 and Signal via STAT3 to Promote Expansion of human Hepatocellular Carcinoma Stem Cells,” Gastroenterology 147, no. 6 (2014): 1393–1404.

[65] Y. Li, R. Wang, S. Xiong, et al., “Cancer-associated Fibroblasts Promote the Stemness of CD24(+) Liver Cells via Paracrine Signaling,” Journal of molecular medicine (Berlin) 97, no. 2 (2019): 243–255.

[66] Q. Niu, S. Ye, L. Zhao, Y. Qian, and F. Liu, “The Role of Liver Cancer Stem Cells in Hepatocellular Carcinoma Metastasis,” Cancer Biology & Therapy 25, no. 1 (2024): 2321768.

[67] C. Brezden-Masley and C. Polenz, “Current Practices and Challenges of Adjuvant Chemotherapy in Patients With Colorectal Cancer,” Surgical Oncology Clinics of North America 23, no. 1 (2014): 49–58.

[68] K. V. D. Jeught, H. Xu, Y. Li, X. Lu, and G. Ji, “Drug Resistance and New Therapies in Colorectal Cancer,” World Journal of Gastroenterology 24, no. 34 (2018): 3834–3848.

[69] T. Huang, X. Song, D. Xu, et al., “Stem Cell Programs in Cancer Initiation, Progression, and Therapy Resistance,” Theranostics 10, no. 19 (2020): 8721–8743.

[70] C. Sethy and C. Kundu, “Fluorouracil (5-FU) Resistance and the New Strategy to Enhance the Sensitivity Against Cancer: Implication of DNA Repair Inhibition,” Biomedicine & Pharmacotherapy 137 (2021): 111285.

[71] M. Todaro, M. P. Alea, A. B. Di Stefano, et al., “Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4,” Cell Stem Cell 1, no. 4 (2007): 389–402.

[72] X. Lei, Q. He, Z. Li, et al., “Cancer Stem Cells in Colorectal Cancer and the Association With Chemotherapy Resistance,” Medical Oncology 38, no. 4 (2021): 43.

[73] N. Hashimoto, R. Tsunedomi, K. Yoshimura, Y. Watanabe, S. Hazama, and M. Oka, “Cancer Stem-Like Sphere Cells Induced From De-differentiated Hepatocellular Carcinoma-derived Cell Lines Possess the Resistance to Anti-cancer Drugs,” BMC Cancer 14 (2014): 722.

[74] N. Takebe, L. Miele, P. J. Harris, et al., “Targeting Notch, Hedgehog, and Wnt Pathways in Cancer Stem Cells: Clinical Update,” Nature Reviews Clinical Oncology 12, no. 8 (2015): 445–464.

[75] H. Verma, M. Singh Bahia, S. Choudhary, P. Kumar Singh, and O. Silakari, “Drug Metabolizing Enzymes-associated Chemo Resistance and Strategies to Overcome It,” Drug Metabolism Reviews 51, no. 2 (2019): 196–223.

[76] H. Zheng, H. Liu, H. Li, et al., “Characterization of Stem Cell Landscape and Identification of Stemness-relevant Prognostic Gene Signature to Aid Immunotherapy in Colorectal Cancer,” Stem Cell Research & Therapy 13, no. 1 (2022): 244.

[77] Y. Wang, W. Wang, and Z. Sun, “Cancer Stem Cell-immune Cell Collusion in Immunotherapy,” International Journal of Cancer 153, no. 4 (2023): 694–708.

[78] D. Bayik and J. Lathia, “Cancer Stem Cell-immune Cell Crosstalk in Tumour Progression,” Nature Reviews Cancer 21, no. 8 (2021): 526–536.

[79] D. J. Park, P. S. Sung, J. Kim, et al., “EpCAM-high Liver Cancer Stem Cells Resist Natural Killer Cell-mediated Cytotoxicity by Upregulating CEACAM1,” Journal for ImmunoTherapy of Cancer 8, no. 1 (2020): e000301.

[80] Z. Zhu, X. Hao, M. Yan, et al., “Cancer Stem/Progenitor Cells Are Highly Enriched in CD133+CD44+ Population in Hepatocellular Carcinoma,” International Journal of Cancer 126, no. 9 (2010): 2067–2078.

[81] S. Ma, K. W. Chan, T. K. Lee, et al., “Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations,” Molecular Cancer Research 6, no. 7 (2008): 1146–1153.

[82] C. Hu, H. Li, J. Li, et al., “Analysis of ABCG2 Expression and Side Population Identifies Intrinsic Drug Efflux in the HCC Cell Line MHCC-97L and Its Modulation by Akt Signaling,” Carcinogenesis 29, no. 12 (2008): 2289–2297.

[83] N. Haraguchi, T. Utsunomiya, H. Inoue, et al., “Characterization of a Side Population of Cancer Cells From human Gastrointestinal System,” Stem Cells 24, no. 3 (2006): 506–513.

[84] H. Xin, C. M. Ambe, D. M. Hari, et al., “Label-retaining Liver Cancer Cells Are Relatively Resistant to sorafenib,” Gut 62, no. 12 (2013): 1777–1786.

[85] L. S. Piao, W. Hur, T. Kim, et al., “CD133+ liver Cancer Stem Cells Modulate Radioresistance in human Hepatocellular Carcinoma,” Cancer Letters 315, no. 2 (2012): 129–137.

[86] S. Ma, T. K. Lee, B. Zheng, K. W. Chan, and X. Guan, “CD133+ HCC Cancer Stem Cells Confer Chemoresistance by Preferential Expression of the Akt/PKB Survival Pathway,” Oncogene 27, no. 12 (2008): 1749–1758.

[87] A. Fumagalli, K. C. Oost, L. Kester, et al., “Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer,” Cell Stem Cell 26, no. 4 (2020): 569–578. e7.

[88] A. Centonze, A. Roura, M. Novillo-Font, et al., “A Plastic EMP1(+) to LGR5(+) Cell state Conversion as a Bypass to KRAS-G12D Pharmacological Inhibition in Metastatic Colorectal Cancer,” Cancer Discovery (2025).

[89] X. Qin, F. Cardoso Rodriguez, J. Sufi, P. Vlckova, J. Claus, and C. J. Tape, “An Oncogenic Phenoscape of Colonic Stem Cell Polarization,” Cell 186, no. 25 (2023): 5554–5568. e18.

[90] C. Cortina, G. Turon, D. Stork, et al., “A Genome Editing Approach to Study Cancer Stem Cells in human Tumors,” EMBO Molecular Medicine 9, no. 7 (2017): 869–879.

[91] Y. Ohta, M. Fujii, S. Takahashi, et al., “Cell-matrix Interface Regulates Dormancy in human Colon Cancer Stem Cells,” Nature 608, no. 7924 (2022): 784–794.

[92] R. Coppo, J. Kondo, K. Iida, et al., “Distinct but Interchangeable Subpopulations of Colorectal Cancer Cells With Different Growth Fates and Drug Sensitivity,” Iscience 26, no. 2 (2023): 105962.

[93] Y. Kinugasa, T. Matsui, and N. Takakura, “CD44 expressed on Cancer-associated Fibroblasts Is a Functional Molecule Supporting the Stemness and Drug Resistance of Malignant Cancer Cells in the Tumor Microenvironment,” Stem Cells 32, no. 1 (2014): 145–156.

[94] C. Chen, S. Yang, P. Chang, et al., “Cancer-Associated-Fibroblast-Mediated Paracrine and Autocrine SDF-1/CXCR4 Signaling Promotes Stemness and Aggressiveness of Colorectal Cancers,” Cells 13, no. 16 (2024): 1334.

[95] Y. Ma, J. Zhu, S. Chen, et al., “Low Expression of SPARC in Gastric Cancer-associated Fibroblasts Leads to Stemness Transformation and 5-fluorouracil Resistance in Gastric Cancer,” Cancer Cell International 19 (2019): 137.

[96] F. Colella, F. Calapà, G. Artemi, et al., “CD147 Mediates the Metabolic Reprogramming of Cancer Associated Fibroblasts Induced by EVs Released by Differentiating Cancer Stem Cells,” Journal of Extracellular Biology 4, no. 3 (2025): e70039.

[97] Y. Yang, Y. Ma, S. Yan, et al., “CAF Promotes Chemoresistance Through NRP2 in Gastric Cancer,” Gastric Cancer 25, no. 3 (2022): 503–514.

[98] X. Zhou, J. Han, A. Zuo, et al., “THBS2 + cancer-associated Fibroblasts Promote EMT Leading to Oxaliplatin Resistance via COL8A1-mediated PI3K/AKT Activation in Colorectal cancer,” Molecular Cancer 23, no. 1 (2024): 282.

[99] Y. Li, Q. Liu, X. Jing, et al., “Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets,” MedComm 6, no. 7 (2025): e70292.

[100] M. Jinushi, S. Chiba, H. Yoshiyama, et al., “Tumor-associated Macrophages Regulate Tumorigenicity and Anticancer Drug Responses of Cancer Stem/Initiating Cells,” PNAS 108, no. 30 (2011): 12425–12430.

[101] N. Swain, M. Thakur, J. Pathak, S. Patel, and R. Hosalkar, “Aldehyde Dehydrogenase 1: Its Key Role in Cell Physiology and Oral Carcinogenesis,” Dental and Medical Problems 59, no. 4 (2022): 629–635.

[102] Z. Kozovska, A. Patsalias, V. Bajzik, et al., “ALDH1A inhibition Sensitizes Colon Cancer Cells to Chemotherapy,” BMC Cancer 18, no. 1 (2018): 656.

[103] Y. Yang, T. Nguyen, I. Pereira, J. Hur, and H. Kim, “Lichen Secondary Metabolite Physciosporin Decreases the Stemness Potential of Colorectal Cancer Cells,” Biomolecules 9, no. 12 (2019): 797.

[104] M. Vander Heiden, L. Cantley, and C. Thompson, “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation,” Science 324, no. 5930 (2009): 1029–1033.

[105] L. Reinsalu, M. Puurand, V. Chekulayev, et al., “Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis,” Frontiers in Oncology 11 (2021): 698951.

[106] A. Tuerhong, J. Xu, S. Shi, et al., “Overcoming Chemoresistance by Targeting Reprogrammed Metabolism: The Achilles' heel of Pancreatic Ductal Adenocarcinoma,” Cellular and Molecular Life Sciences 78, no. 14 (2021): 5505–5526.

[107] D. Tavares-Valente, S. Cannone, M. R. Greco, et al., “Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell,” Cancers (Basel) 15, no. 15 (2023): 3868.

[108] B. Chakravarti, J. Akhtar Siddiqui, R. Anthony Sinha, and S. Raza, “Targeting Autophagy and Lipid Metabolism in Cancer Stem Cells,” Biochemical Pharmacology 212 (2023): 115550.

[109] K. Qureshi-Baig, P. Ullmann, S. Haan, and E. Letellier, “Tumor-Initiating Cells: A criTICal Review of Isolation Approaches and New Challenges in Targeting Strategies,” Molecular Cancer 16, no. 1 (2017): 40.

[110] G. I. Botchkina, E. S. Zuniga, M. Das, et al., “New-generation Taxoid SB-T-1214 Inhibits Stem Cell-related Gene Expression in 3D Cancer Spheroids Induced by Purified Colon Tumor-initiating Cells,” Molecular Cancer 9 (2010): 192.

[111] P. D. Dunne, S. Dasgupta, J. K. Blayney, et al., “EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer,” Clinical Cancer Research 22, no. 1 (2016): 230–242.

[112] A. Merlos-Suárez, F. Barriga, P. Jung, et al., “The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse,” Cell Stem Cell 8, no. 5 (2011): 511–524.

[113] J. Jang, Y. Song, S. Kim, et al., “CD133 confers Cancer Stem-Like Cell Properties by Stabilizing EGFR-AKT Signaling in Hepatocellular Carcinoma,” Cancer Letters 389 (2017): 1–10.

[114] J. Wang, J. Liao, Y. Cheng, M. Chen, and A. Huang, “LAPTM4B enhances the Stemness of CD133(+) Liver Cancer Stem-Like Cells via WNT/Beta-catenin Signaling,” JHEP Reports 7, no. 4 (2025): 101306.

[115] K. Dzobo and M. Sinkala, “Cancer Stem Cell Marker CD44 Plays Multiple Key Roles in Human Cancers: Immune Suppression/Evasion, Drug Resistance, Epithelial-Mesenchymal Transition, and Metastasis,” Omics 25, no. 5 (2021): 313–332.

[116] L. Patrawala, T. Calhoun, R. Schneider-Broussard, et al., “Highly Purified CD44+ Prostate Cancer Cells From Xenograft human Tumors Are Enriched in Tumorigenic and Metastatic Progenitor Cells,” Oncogene 25, no. 12 (2006): 1696–1708.

[117] M. Nakano, Y. Kikushige, K. Miyawaki, et al., “Dedifferentiation Process Driven by TGF-beta Signaling Enhances Stem Cell Properties in human Colorectal Cancer,” Oncogene 38, no. 6 (2019): 780–793.

[118] J. Ji, X. Zheng, M. Forgues, et al., “Identification of microRNAs Specific for Epithelial Cell Adhesion Molecule-positive Tumor Cells in Hepatocellular Carcinoma,” Hepatology 62, no. 3 (2015): 829–840.

[119] K. S. Yan, C. Y. Janda, J. Chang, et al., “Non-equivalence of Wnt and R-spondin Ligands During Lgr5(+) Intestinal Stem-cell Self-renewal,” Nature 545, no. 7653 (2017): 238–242.

[120] N. Barker, J. H. van Es, J. Kuipers, et al., “Identification of Stem Cells in Small Intestine and Colon by Marker Gene Lgr5,” Nature 449, no. 7165 (2007): 1003–1007.

[121] E. Vreugdenhil, S. M. Kolk, K. Boekhoorn, et al., “Doublecortin-Like, a Microtubule-associated Protein Expressed in Radial Glia, Is Crucial for Neuronal Precursor Division and Radial Process Stability,” European Journal of Neuroscience 25, no. 3 (2007): 635–648.

[122] T. Shu, H. Tseng, T. Sapir, et al., “Doublecortin-Like Kinase Controls Neurogenesis by Regulating Mitotic Spindles and M Phase Progression,” Neuron 49, no. 1 (2006): 25–39.

[123] Y. Nakanishi, H. Seno, A. Fukuoka, et al., “Dclk1 distinguishes Between Tumor and Normal Stem Cells in the Intestine,” Nature Genetics 45, no. 1 (2013): 98–103.

[124] M. Bowen, A. Aruffo, and J. Bajorath, “Cell Surface Receptors and Their Ligands: In Vitro Analysis of CD6-CD166 Interactions,” Proteins 40, no. 3 (2000): 420–428.

[125] N. HARAGUCHI, H. ISHII, K. MIMORI, et al., “CD49f-positive Cell Population Efficiently Enriches Colon Cancer-initiating Cells,” International Journal of Oncology 43, no. 2 (2013): 425–430.

[126] C. Yang, H. Geng, X. Yang, et al., “Targeting the Immune Privilege of Tumor-initiating Cells to Enhance Cancer Immunotherapy,” Cancer Cell 42, no. 12 (2024): 2064–2081. e19.

[127] D. Choi, H. W. Lee, K. Y. Hur, et al., “Cancer Stem Cell Markers CD133 and CD24 Correlate With Invasiveness and Differentiation in Colorectal Adenocarcinoma,” World Journal of Gastroenterology 15, no. 18 (2009): 2258–2264.

[128] J. Huang, M. Oshi, I. Endo, and K. Takabe, “Clinical Relevance of Stem Cell Surface Markers CD133, CD24, and CD44 in Colorectal Cancer,” American Journal of Cancer Research 11, no. 10 (2021): 5141–5154.

[129] Y. Jiang, A. Sun, Y. Zhao, et al., “Proteomics Identifies New Therapeutic Targets of Early-stage Hepatocellular Carcinoma,” Nature 567, no. 7747 (2019): 257–261.

[130] J. G. Paez, P. A. Jänne, J. C. Lee, et al., “EGFR Mutations in Lung Cancer: Correlation With Clinical Response to gefitinib Therapy,” Science 304, no. 5676 (2004): 1497–1500.

[131] M. Takada and M. Toi, “Neoadjuvant Treatment for HER2-positive Breast Cancer,” Chinese Clinical Oncology 9, no. 3 (2020): 32.

[132] Q. Lu, H. Feng, H. Chen, et al., “Role of DCLK1 in Oncogenic Signaling (Review),” International Journal of Oncology 61, no. 5 (2022): 137.

[133] C. Scharenberg, M. Harkey, and B. Torok-Storb, “The ABCG2 Transporter Is an Efficient Hoechst 33342 Efflux Pump and Is Preferentially Expressed by Immature human Hematopoietic Progenitors,” Blood 99, no. 2 (2002): 507–512.

[134] L. Feng, J. Wu, and F. Yi, “Isolation and Phenotypic Characterization of Cancer Stem-Like Side Population Cells in Colon Cancer,” Molecular Medicine Reports 12, no. 3 (2015): 3531–3536.

[135] A. Golebiewska, N. H. Brons, R. Bjerkvig, and S. P. Niclou, “Critical Appraisal of the Side Population Assay in Stem Cell and Cancer Stem Cell Research,” Cell Stem Cell 8, no. 2 (2011): 136–147.

[136] P. Marcato, C. A. Dean, C. A. Giacomantonio, and P. W. Lee, “Aldehyde Dehydrogenase: Its Role as a Cancer Stem Cell Marker Comes Down to the Specific Isoform,” Cell Cycle 10, no. 9 (2011): 1378–1384.

[137] E. H. Huang, M. J. Hynes, T. Zhang, et al., “Aldehyde Dehydrogenase 1 Is a Marker for Normal and Malignant human Colonic Stem Cells (SC) and Tracks SC Overpopulation During Colon Tumorigenesis,” Cancer Research 69, no. 8 (2009): 3382–3389.

[138] H. Feng, Y. Liu, X. Bian, F. Zhou, and Y. Liu, “ALDH1A3 affects Colon Cancer in Vitro Proliferation and Invasion Depending on CXCR4 Status,” British Journal of Cancer 118, no. 2 (2018): 224–232.

[139] L. Mele, D. Liccardo, and V. Tirino, “Evaluation and Isolation of Cancer Stem Cells Using ALDH Activity Assay,” Methods in Molecular Biology 1692 (2018): 43–48.

[140] L. Weiswald, D. Bellet, and V. Dangles-Marie, “Spherical Cancer Models in Tumor Biology,” Neoplasia 17, no. 1 (2015): 1–15.

[141] T. Sato, D. E. Stange, M. Ferrante, et al., “Long-term Expansion of Epithelial Organoids From human Colon, Adenoma, Adenocarcinoma, and Barrett's Epithelium,” Gastroenterology 141, no. 5 (2011): 1762–1772.

[142] G. Zhou, X. Lv, X. Zhong, et al., “Suspension Culture Strategies to Enrich Colon Cancer Stem Cells,” Oncology Letters 25, no. 3 (2023): 116.

[143] B. L. LeSavage, R. A. Suhar, N. Broguiere, M. P. Lutolf, and S. C. Heilshorn, “Next-generation Cancer Organoids,” Nature Materials 21, no. 2 (2022): 143–159.

[144] I. Miranda-Lorenzo, J. Dorado, E. Lonardo, et al., “Intracellular Autofluorescence: A Biomarker for Epithelial Cancer Stem Cells,” Nature Methods 11, no. 11 (2014): 1161–1169.

[145] J. Vieira de Castro, C. S. Gonçalves, E. P. Martins, et al., “Intracellular Autofluorescence as a New Biomarker for Cancer Stem Cells in Glioblastoma,” Cancers (Basel) 13, no. 4 (2021): 828.

[146] N. Pajuelo-Lozano, S. Alcalá, B. Sainz, R. Perona, and I. Sanchez-Perez, “Targeting MAD2 Modulates Stemness and Tumorigenesis in human Gastric Cancer Cell Lines,” Theranostics 10, no. 21 (2020): 9601–9618.

[147] M. Marzagalli, R. M. Moretti, E. Messi, et al., “Targeting Melanoma Stem Cells With the Vitamin E Derivative δ-tocotrienol,” Scientific Reports 8, no. 1 (2018): 587.

[148] S. Alcala, G. Serralta San Martin, M. Muñoz-Fernández de Legaria, et al., “Autofluorescent Cancer Stem Cells: Potential Biomarker to Predict Recurrence in Resected Colorectal Tumors,” Cancer Research Communications 4, no. 10 (2024): 2575–2588.

[149] B. Salik, H. Yi, N. Hassan, et al., “Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia,” Cancer Cell 38, no. 2 (2020): 263–278. e6.

[150] J. P. Soleas, E. D'Arcangelo, L. Huang, et al., “Assembly of Lung Progenitors Into Developmentally-inspired Geometry Drives Differentiation via Cellular Tension,” Biomaterials 254 (2020): 120128.

[151] R. Nusse and H. Clevers, “Wnt/Beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities,” Cell 169, no. 6 (2017): 985–999.

[152] M. Zhang, W. Weng, Q. Zhang, et al., “The lncRNA NEAT1 Activates Wnt/β-catenin Signaling and Promotes Colorectal Cancer Progression via Interacting With DDX5,” Journal of hematology & oncology 11, no. 1 (2018): 113.

[153] M. Cao, A. You, X. Zhu, et al., “miR-182-5p Promotes Hepatocellular Carcinoma Progression by Repressing FOXO3a,” Journal of hematology & oncology 11, no. 1 (2018): 12.

[154] X. Ge and X. Wang, “Role of Wnt Canonical Pathway in Hematological Malignancies,” Journal of hematology & oncology 3 (2010): 33.

[155] S. He and S. Tang, “WNT/β-catenin Signaling in the Development of Liver Cancers,” Biomedicine & Pharmacotherapy 132 (2020): 110851.

[156] A. Gajos-Michniewicz and M. Czyz, “WNT Signaling in Melanoma,” International Journal of Molecular Sciences 21, no. 14 (2020): 4852.

[157] R. Najdi, K. Proffitt, S. Sprowl, et al., “A Uniform human Wnt Expression Library Reveals a Shared Secretory Pathway and Unique Signaling Activities,” Differentiation 84, no. 2 (2012): 203–213.

[158] M. Cao, Y. Deng, Q. Hao, et al., “Single-cell Transcriptomic Analysis Reveals Gut Microbiota-immunotherapy Synergy Through Modulating Tumor Microenvironment,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 140.

[159] H. Clevers, K. Loh, and R. Nusse, “Stem Cell Signaling. An Integral Program for Tissue Renewal and Regeneration: Wnt Signaling and Stem Cell Control,” Science 346, no. 6205 (2014): 1248012.

[160] K. Wiese, R. Nusse, and R. van Amerongen, “Wnt Signalling: Conquering Complexity,” Development (Cambridge, England) 145, no. 12 (2018): dev165902.

[161] R. Nusse and H. Clevers, “Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities,” Cell 169, no. 6 (2017): 985–999.

[162] J. Bilić, Y. Huang, G. Davidson, et al., “Wnt Induces LRP6 Signalosomes and Promotes Dishevelled-dependent LRP6 Phosphorylation,” Science 316, no. 5831 (2007): 1619–1622.

[163] C. Alexandre, A. Baena-Lopez, and J. Vincent, “Patterning and Growth Control by Membrane-tethered Wingless,” Nature 505, no. 7482 (2014): 180–185.

[164] P. Zhu, J. Wu, Y. Wang, et al., “LncGata6 maintains Stemness of Intestinal Stem Cells and Promotes Intestinal Tumorigenesis,” Nature Cell Biology 20, no. 10 (2018): 1134–1144.

[165] Q. Tang, J. Chen, Z. Di, et al., “TM4SF1 promotes EMT and Cancer Stemness via the Wnt/Beta-catenin/SOX2 Pathway in Colorectal Cancer,” Journal of Experimental & Clinical Cancer Research 39, no. 1 (2020): 232.

[166] F. Hua, S. Shang, Y. Yang, et al., “TRIB3 Interacts with Beta-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis,” Gastroenterology 156, no. 3 (2019): 708–721. e15.

[167] H. W. Leung, C. O. N. Leung, E. Y. Lau, et al., “EPHB2 Activates Beta-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma,” Cancer Research 81, no. 12 (2021): 3229–3240.

[168] Y. Tao, B. Kang, D. A. Petkovich, et al., “Aging-Like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf(V600E)-Induced Tumorigenesis,” Cancer Cell 35, no. 2 (2019): 315–328. e6.

[169] J. W. Park, J. M. Park, D. M. Park, D. Kim, and H. K. Kim, “Stem Cells Antigen-1 Enriches for a Cancer Stem Cell-Like Subpopulation in Mouse Gastric Cancer,” Stem Cells 34, no. 5 (2016): 1177–1187.

[170] D. J. Flanagan, N. Pentinmikko, K. Luopajärvi, et al., “NOTUM From Apc-mutant Cells Biases Clonal Competition to Initiate Cancer,” Nature 594, no. 7863 (2021): 430–435.

[171] P. Ordóñez-Morán, C. Dafflon, M. Imajo, E. Nishida, and J. Huelsken, “HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer,” Cancer Cell 28, no. 6 (2015): 815–829.

[172] X. Wang, J. Moon, M. E. Dodge, et al., “The Development of Highly Potent Inhibitors for Porcupine,” Journal of Medicinal Chemistry 56, no. 6 (2013): 2700–2704.

[173] Z. Liu, P. Wang, E. A. Wold, et al., “Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer,” Journal of Medicinal Chemistry 64, no. 8 (2021): 4257–4288.

[174] X. Cheng, X. Xu, D. Chen, F. Zhao, and W. Wang, “Therapeutic Potential of Targeting the Wnt/β-catenin Signaling Pathway in Colorectal Cancer,” Biomedicine & Pharmacotherapy 110 (2019): 473–481.

[175] A. Chruścik, V. Gopalan, and A. K. Lam, “The Clinical and Biological Roles of Transforming Growth Factor Beta in Colon Cancer Stem Cells: A Systematic Review,” European Journal of Cell Biology 97, no. 1 (2018): 15–22.

[176] D. Abetov, Z. Mustapova, T. Saliev, and D. Bulanin, “Biomarkers and Signaling Pathways of Colorectal Cancer Stem Cells,” Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine 36, no. 3 (2015): 1339–1353.

[177] K. Tzavlaki and A. Moustakas, “TGF-beta Signaling,” Biomolecules 10, no. 3 (2020): 487.

[178] S. S. Yusra and H. Yokozaki, “Biological Significance of Tumor Budding at the Invasive front of human Colorectal Carcinoma Cells,” International Journal of Oncology 41, no. 1 (2012): 201–210.

[179] A. Malfettone, J. Soukupova, E. Bertran, et al., “Transforming Growth Factor-beta-induced Plasticity Causes a Migratory Stemness Phenotype in Hepatocellular Carcinoma,” Cancer Letters 392 (2017): 39–50.

[180] Y. Katsuno, S. Lamouille, and R. Derynck, “TGF-β Signaling and Epithelial-mesenchymal Transition in Cancer Progression,” Current Opinion in Oncology 25, no. 1 (2013): 76–84.

[181] A. Malfettone, J. Soukupova, E. Bertran, et al., “Transforming Growth Factor-β-induced Plasticity Causes a Migratory Stemness Phenotype in Hepatocellular Carcinoma,” Cancer Letters 392 (2017): 39–50.

[182] Y. Zhang, Q. Li, H. Liu, et al., “MKRN1 promotes Colorectal Cancer Metastasis by Activating the TGF-beta Signalling Pathway Through SNIP1 Protein Degradation,” Journal of Experimental & Clinical Cancer Research 42, no. 1 (2023): 219.

[183] M. Futakuchi, K. Lami, Y. Tachibana, Y. Yamamoto, M. Furukawa, and J. Fukuoka, “The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment,” International Journal of Molecular Sciences 20, no. 20 (2019): 5117.

[184] R. Akhurst and A. Hata, “Targeting the TGFβ Signalling Pathway in Disease,” Nature Reviews Drug Discovery 11, no. 10 (2012): 790–811.

[185] B. Kim, Y. Seo, J. Kwon, et al., “IL-6 and IL-8, Secreted by Myofibroblasts in the Tumor Microenvironment, Activate HES1 to Expand the Cancer Stem Cell Population in Early Colorectal Tumor,” Molecular Carcinogenesis 60, no. 3 (2021): 188–200.

[186] B. Kim, E. Malek, S. H. Choi, J. J. Ignatz-Hoover, and J. J. Driscoll, “Novel Therapies Emerging in Oncology to Target the TGF-β Pathway,” Journal of Hematology & Oncology 14, no. 1 (2021): 55.

[187] C. Bellomo, L. Caja, and A. Moustakas, “Transforming Growth Factor β as Regulator of Cancer Stemness and Metastasis,” British Journal of Cancer 115, no. 7 (2016): 761–769.

[188] A. Calon, E. Lonardo, A. Berenguer-Llergo, et al., “Stromal Gene Expression Defines Poor-prognosis Subtypes in Colorectal Cancer,” Nature Genetics 47, no. 4 (2015): 320–329.

[189] D. V. F. Tauriello, S. Palomo-Ponce, D. Stork, et al., “TGFbeta Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis,” Nature 554, no. 7693 (2018): 538–543.

[190] M. Fasano, M. Pirozzi, C. C. Miceli, et al., “TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities,” International Journal of Molecular Sciences 25, no. 13 (2024): 7400.

[191] V. R. Silva, L. D. S. Santos, R. B. Dias, C. A. Quadros, and D. P. Bezerra, “Emerging Agents That Target Signaling Pathways to Eradicate Colorectal Cancer Stem Cells,” Cancer communications (London) 41, no. 12 (2021): 1275–1313.

[192] H. Yu, H. Lee, A. Herrmann, R. Buettner, and R. Jove, “Revisiting STAT3 Signalling in Cancer: New and Unexpected Biological Functions,” Nature Reviews Cancer 14, no. 11 (2014): 736–746.

[193] H. Qayoom, N. A. Wani, B. Alshehri, and M. A. Mir, “An Insight Into the Cancer Stem Cell Survival Pathways Involved in Chemoresistance in Triple-negative Breast Cancer,” Future oncology 17, no. 31 (2021): 4185–4206.

[194] C. Li, M. Zhu, J. Zhu, et al., “SOX12 contributes to the Activation of the JAK2/STAT3 Pathway and Malignant Transformation of Esophageal Squamous Cell Carcinoma,” Oncology Reports 45, no. 1 (2021): 129–138.

[195] P. Xin, X. Xu, C. Deng, et al., “The Role of JAK/STAT Signaling Pathway and Its Inhibitors in Diseases,” International Immunopharmacology 80 (2020): 106210.

[196] P. Murray, “The JAK-STAT Signaling Pathway: Input and Output Integration,” Journal of Immunology 178, no. 5 (2007): 2623–2629.

[197] Q. Hu, Q. Bian, D. Rong, et al., “JAK/STAT Pathway: Extracellular Signals, Diseases, Immunity, and Therapeutic Regimens,” Frontiers in Bioengineering and Biotechnology 11 (2023): 1110765.

[198] H. Xiong, J. Hong, W. Du, et al., “Roles of STAT3 and ZEB1 Proteins in E-cadherin Down-regulation and human Colorectal Cancer Epithelial-mesenchymal Transition,” Journal of Biological Chemistry 287, no. 8 (2012): 5819–5832.

[199] D. Chaker, C. Desterke, N. Moniaux, et al., “Direct Reprogramming of Hepatocytes into JAK/Stat-Dependent LGR5+ Liver Cells Able to Initiate Intrahepatic Cholangiocarcinoma,” Stem Cells 42, no. 4 (2024): 301–316.

[200] Y. Su, H. Lai, Y. Chang, G. Chen, and J. Lee, “Direct Reprogramming of Stem Cell Properties in Colon Cancer Cells by CD44,” Embo Journal 30, no. 15 (2011): 3186–3199.

[201] S. Park, C. Lee, J. Choi, et al., “The JAK2/STAT3/CCND2 Axis Promotes Colorectal Cancer Stem Cell Persistence and Radioresistance,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 399.

[202] T. B. Toh, J. J. Lim, L. Hooi, M. B. M. A. Rashid, and E. K. Chow, “Targeting Jak/Stat Pathway as a Therapeutic Strategy Against SP/CD44+ Tumorigenic Cells in Akt/β-catenin-driven Hepatocellular Carcinoma,” Journal of Hepatology 72, no. 1 (2020): 104–118.

[203] C. Jiang, J. Long, B. Liu, et al., “miR-500a-3p Promotes Cancer Stem Cells Properties via STAT3 Pathway in human Hepatocellular Carcinoma,” Journal of Experimental & Clinical Cancer Research 36, no. 1 (2017): 99.

[204] S. Artavanis-Tsakonas, M. Muskavitch, and B. Yedvobnick, “Molecular Cloning of Notch, a Locus Affecting Neurogenesis in Drosophila Melanogaster,” PNAS 80, no. 7 (1983): 1977–1981.

[205] T. Noah and N. Shroyer, “Notch in the Intestine: Regulation of Homeostasis and Pathogenesis,” Annual Review of Physiology 75 (2013): 263–288.

[206] C. Meisel, C. Porcheri, and T. Mitsiadis, “Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression,” Cells 9, no. 8 (2020): 1879.

[207] L. Yang, P. Shi, G. Zhao, et al., “Targeting Cancer Stem Cell Pathways for Cancer Therapy,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 8.

[208] G. van Tetering, P. van Diest, I. Verlaan, E. van der Wall, R. Kopan, and M. Vooijs, “Metalloprotease ADAM10 Is Required for Notch1 Site 2 Cleavage,” Journal of Biological Chemistry 284, no. 45 (2009): 31018–31027.

[209] G. Moldovan, L. Miele, and A. Fazleabas, “Notch Signaling in Reproduction,” Trends in Endocrinology and Metabolism 32, no. 12 (2021): 1044–1057.

[210] E. Demitrack and L. Samuelson, “Notch Regulation of Gastrointestinal Stem Cells,” The Journal of Physiology 594, no. 17 (2016): 4791–4803.

[211] R. Kar, S. K. Jha, S. Ojha, et al., “The FBXW7-NOTCH Interactome: A Ubiquitin Proteasomal System-induced Crosstalk Modulating Oncogenic Transformation in human Tissues,” Cancer Reports (Hoboken) 4, no. 4 (2021): e1369.

[212] M. Li, C. Zhu, T. Ling, et al., “FBXW7 expression Is Associated With Prognosis and Chemotherapeutic Outcome in Chinese Patients With Gastric Adenocarcinoma,” BMC Gastroenterology [Electronic Resource] 17, no. 1 (2017): 60.

[213] K. Segami, T. Aoyama, Y. Hiroshima, et al., “Clinical Significance of TAP1 and DLL4 Expression in Patients with Locally Advanced Gastric Cancer,” In Vivo (Athens, Greece) 35, no. 5 (2021): 2771–2777.

[214] W. Feifei, G. Hui, Z. Ruiqiang, J. Qunxiang, and X. Yu'an, “MAGP2, a Component of Extracellular Matrix, Is Upregulated in Colorectal Cancer and Negatively Modulated by miR-200b-3p,” Technology in Cancer Research & Treatment 18 (2019): 1533033819870777.

[215] M. Wang, L. Tang, S. Chen, et al., “ZNF217-activated Notch Signaling Mediates Sulforaphane-suppressed Stem Cell Properties in Colorectal Cancer,” Journal of Nutritional Biochemistry 125 (2024): 109551.

[216] R. Wang, Y. Li, A. Tsung, et al., “iNOS Promotes CD24(+)CD133(+) Liver Cancer Stem Cell Phenotype Through a TACE/ADAM17-dependent Notch Signaling Pathway,” PNAS 115, no. 43 (2018): E10127–E10136.

[217] E. S. Demitrack, G. B. Gifford, T. M. Keeley, et al., “Notch Signaling Regulates Gastric Antral LGR5 Stem Cell Function,” Embo Journal 34, no. 20 (2015): 2522–2536.

[218] X. Yuan, H. Wu, H. Xu, et al., “Notch Signaling: An Emerging Therapeutic Target for Cancer Treatment,” Cancer Letters 369, no. 1 (2015): 20–27.

[219] I. Espinoza and L. Miele, “Notch Inhibitors for Cancer Treatment,” Pharmacology & Therapeutics 139, no. 2 (2013): 95–110.

[220] S. Ponnurangam, J. M. Mammen, S. Ramalingam, et al., “Honokiol in Combination With Radiation Targets Notch Signaling to Inhibit Colon Cancer Stem Cells,” Molecular Cancer Therapeutics 11, no. 4 (2012): 963–972.

[221] P. A. Beachy, S. G. Hymowitz, R. A. Lazarus, D. J. Leahy, and C. Siebold, “Interactions Between Hedgehog Proteins and Their Binding Partners Come Into View,” Genes & development 24, no. 18 (2010): 2001–2012.

[222] C. Odoux, H. Fohrer, T. Hoppo, et al., “A Stochastic Model for Cancer Stem Cell Origin in Metastatic Colon Cancer,” Cancer Research 68, no. 17 (2008): 6932–6941.

[223] J. Ng and T. Curran, “The Hedgehog's Tale: Developing Strategies for Targeting Cancer,” Nature Reviews Cancer 11, no. 7 (2011): 493–501.

[224] E. Lima-Fernandes, A. Murison, T. da Silva Medina, et al., “Targeting Bivalency De-represses Indian Hedgehog and Inhibits Self-renewal of Colorectal Cancer-initiating Cells,” Nature Communications 10, no. 1 (2019): 1436.

[225] B. R. Kim, Y. J. Na, J. L. Kim, et al., “RUNX3 suppresses Metastasis and Stemness by Inhibiting Hedgehog Signaling in Colorectal Cancer,” Cell Death and Differentiation 27, no. 2 (2020): 676–694.

[226] H. Zhou, Y. Xiong, L. Peng, R. Wang, H. Zhang, and Z. Fu, “LncRNA-cCSC1 Modulates Cancer Stem Cell Properties in Colorectal Cancer via Activation of the Hedgehog Signaling Pathway,” Journal of Cellular Biochemistry 121, no. 3 (2020): 2510–2524.

[227] Y. Gu, Y. Wang, L. He, et al., “Circular RNA circIPO11 Drives Self-renewal of Liver Cancer Initiating Cells via Hedgehog Signaling,” Molecular Cancer 20, no. 1 (2021): 132.

[228] C. Liu, C. Lan, J. Chou, T. Tseng, and W. Liao, “CHSY1 promotes Aggressive Phenotypes of Hepatocellular Carcinoma Cells via Activation of the Hedgehog Signaling Pathway,” Cancer Letters 403 (2017): 280–288.

[229] W. Cheng, K. Xu, D. Y. Tian, Z. G. Zhang, L. J. Liu, and Y. Chen, “Role of Hedgehog Signaling Pathway in Proliferation and Invasiveness of Hepatocellular Carcinoma Cells,” International Journal of Oncology 34, no. 3 (2009): 829–836.

[230] W. Jeng, I. Sheen, M. Yu, et al., “Activation of the Sonic Hedgehog Signaling Pathway Occurs in the CD133 Positive Cells of Mouse Liver Cancer Hepa 1-6 Cells,” OncoTargets and Therapy 6 (2013): 1047–1055.

[231] K. Jeng, C. Jeng, W. Jeng, et al., “Sonic Hedgehog Pathway Inhibitor Mitigates Mouse Hepatocellular Carcinoma,” American Journal of Surgery 210, no. 3 (2015): 554–560.

[232] K. Jeng, C. Chang, and S. Lin, “Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments,” International Journal of Molecular Sciences 21, no. 3 (2020): 758.

[233] S. Scales and F. de Sauvage, “Mechanisms of Hedgehog Pathway Activation in Cancer and Implications for Therapy,” Trends in Pharmacological Sciences 30, no. 6 (2009): 303–312.

[234] E. J. Kim, V. Sahai, E. V. Abel, et al., “Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (vismodegib) in Combination With gemcitabine in Patients With Metastatic Pancreatic Adenocarcinoma,” Clinical Cancer Research 20, no. 23 (2014): 5937–5945.

[235] J. Berlin, J. C. Bendell, L. L. Hart, et al., “A Randomized Phase II Trial of vismodegib versus Placebo With FOLFOX or FOLFIRI and Bevacizumab in Patients With Previously Untreated Metastatic Colorectal Cancer,” Clinical Cancer Research 19, no. 1 (2013): 258–267.

[236] B. Batsaikhan, K. Yoshikawa, N. Kurita, et al., “Cyclopamine Decreased the Expression of Sonic Hedgehog and Its Downstream Genes in Colon Cancer Stem Cells,” Anticancer Research 34, no. 11 (2014): 6339–6344.

[237] A. Hanna and L. Shevde, “Hedgehog Signaling: Modulation of Cancer Properies and Tumor Mircroenvironment,” Molecular cancer 15 (2016): 24.

[238] L. Arabi, A. Badiee, F. Mosaffa, and M. R. Jaafari, “Targeting CD44 Expressing Cancer Cells With Anti-CD44 Monoclonal Antibody Improves Cellular Uptake and Antitumor Efficacy of Liposomal Doxorubicin,” J Control Release 220, no. Pt A (2015): 275–286.

[239] C. W. Menke-van der Houven van Oordt, C. Gomez-Roca, C. van Herpen, et al., “First-in-human Phase I Clinical Trial of RG7356, an Anti-CD44 Humanized Antibody, in Patients With Advanced, CD44-expressing Solid Tumors,” Oncotarget 7, no. 48 (2016): 80046–80058.

[240] F. Andrade, D. Rafael, M. Vilar-Hernández, et al., “Polymeric Micelles Targeted Against CD44v6 Receptor Increase Niclosamide Efficacy Against Colorectal Cancer Stem Cells and Reduce Circulating Tumor Cells in Vivo,” Journal of Control Release 331 (2021): 198–212.

[241] S. Patel, B. Waghela, K. Shah, et al., “Silibinin, a Natural Blend in Polytherapy Formulation for Targeting Cd44v6 Expressing Colon Cancer Stem Cells,” Scientific Reports 8, no. 1 (2018): 16985.

[242] D. Li, X. Guo, K. Yang, et al., “EpCAM-targeting CAR-T Cell Immunotherapy Is Safe and Efficacious for Epithelial Tumors,” Science Advances 9, no. 48 (2023): eadg9721.

[243] A. V. Salnikov, N. P. Bretz, C. Perne, et al., “Antibody Targeting of CD24 Efficiently Retards Growth and Influences Cytokine Milieu in Experimental Carcinomas,” British Journal of Cancer 108, no. 7 (2013): 1449–1459.

[244] E. Sagiv, A. Starr, U. Rozovski, et al., “Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA,” Cancer Research 68, no. 8 (2008): 2803–2812.

[245] S. Shapira, A. Shapira, A. Starr, et al., “An Immunoconjugate of Anti-CD24 and Pseudomonas Exotoxin Selectively Kills human Colorectal Tumors in Mice,” Gastroenterology 140, no. 3 (2011): 935–946.

[246] Y. Zhang and X. Wang, “Targeting the Wnt/β-catenin Signaling Pathway in Cancer,” Journal of hematology & oncology 13, no. 1 (2020): 165.

[247] T. Lau, E. Chan, M. Callow, et al., “A Novel tankyrase Small-molecule Inhibitor Suppresses APC Mutation-driven Colorectal Tumor Growth,” Cancer Research 73, no. 10 (2013): 3132–3144.

[248] J. Waaler, O. Machon, L. Tumova, et al., “A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice,” Cancer Research 72, no. 11 (2012): 2822–2832.

[249] R. Derynck, S. Turley, and R. Akhurst, “TGFβ Biology in Cancer Progression and Immunotherapy,” Nature reviews Clinical Oncology 18, no. 1 (2021): 9–34.

[250] M. M. Binabaj, F. Asgharzadeh, F. Rahmani, et al., “Vactosertib Potently Improves Anti-tumor Properties of 5-FU for Colon Cancer,” Daru 31, no. 2 (2023): 193–203.

[251] D. J. Jonker, L. Nott, T. Yoshino, et al., “Napabucasin versus Placebo in Refractory Advanced Colorectal Cancer: A Randomised Phase 3 Trial,” Lancet Gastroenterol Hepatol 3, no. 4 (2018): 263–270.

[252] A. Kawazoe, Y. Kuboki, E. Shinozaki, et al., “Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients With Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial),” Clinical Cancer Research 26, no. 22 (2020): 5887–5894.

[253] A. Sekulic, M. R. Migden, A. E. Oro, et al., “Efficacy and Safety of vismodegib in Advanced Basal-cell Carcinoma,” New England Journal of Medicine 366, no. 23 (2012): 2171–2179.

[254] M. Sherman, R. Yu, D. Engle, et al., “Vitamin D Receptor-mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy,” Cell 159, no. 1 (2014): 80–93.

[255] B. B. Patel, R. Sengupta, S. Qazi, et al., “Curcumin Enhances the Effects of 5-fluorouracil and Oxaliplatin in Mediating Growth Inhibition of Colon Cancer Cells by Modulating EGFR and IGF-1R,” International Journal of Cancer 122, no. 2 (2008): 267–273.

[256] R. T. Gray, M. M. Cantwell, H. G. Coleman, et al., “Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study,” Clinical and Translational Gastroenterology 8, no. 4 (2017): e91.

[257] M. Wickström, C. Dyberg, J. Milosevic, et al., “Wnt/Beta-catenin Pathway Regulates MGMT Gene Expression in Cancer and Inhibition of Wnt Signalling Prevents Chemoresistance,” Nature Communications 6 (2015): 8904.

[258] J. C. Baranda, D. Robbrecht, R. Sullivan, et al., “Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of SAR439459, a TGFbeta Inhibitor, as Monotherapy and in Combination With cemiplimab in Patients With Advanced Solid Tumors: Findings From a Phase 1/1b Study,” Clinical and Translational Science 17, no. 6 (2024): e13854.

[259] V. K. Morris, M. J. Overman, M. Lam, et al., “Bintrafusp Alfa, an Anti-PD-L1:TGF-beta Trap Fusion Protein, in Patients With ctDNA-positive, Liver-limited Metastatic Colorectal Cancer,” Cancer Research Communications no. 9 (2022): 979–986.

[260] A. W. Tolcher, W. A. Messersmith, S. M. Mikulski, et al., “Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors,” Journal of Clinical Oncology 30, no. 19 (2012): 2348–2353.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.