Introduction
Solid tumors are composed of tumor cells and stromal cells including lymphatic endothelial cells (LEC), which are mainly viewed as cells forming lymphatic vessels involved in the transport of metastatic and immune cells. In the process of metastasis, tumor cells need to acquire motility features that imply at least a partial epithelial-to-mesenchymal transition and the capacity to degrade the basement membrane. In addition, in the metastasis of lymph node, there were many complex mechanisms through which tumors engage lymphatic transport and condition tumor-draining lymph nodes, such as extracellular vesicles for pre-metastatic niches.
Cancer cell endothelialization has emerged as a key area of research in recent years. This process involves the gradual transformation of cancer cells into endothelial-like cells, contributing to the formation of tumor-associated blood and lymphatic vasculature. These transformations occur through complex cellular and molecular mechanisms, either within the in vivo tumor microenvironment or under controlled in vitro experimental conditions.1–3 Since these endothelial cells retain certain characteristics of cancer cells, this phenomenon is also referred to as endothelial cell cancerization, representing different perspectives on the initiating and terminal phases of the same biological event. The formation of neovascular and lymphatic structures via cancer cell endothelialization has been observed in various human cancers and animal models. Recent studies indicate that during tumor development, a significant proportion of endothelial cells lining the luminal surfaces of newly formed blood and lymphatic vessels originate from tumor-derived endothelial cells. Specifically, endothelial cells formed through cancer cell endothelialization may account for up to 70% of the endothelial population within tumor-associated lymphatic vasculature.2–4
Cancer cell endothelialization is broadly classified under epithelial-endothelial transition (EET) and epithelial-mesenchymal transition (EMT).5–7 Recent studies have shown that cancer stem cells (CSCs) and EET, a subtype of EMT, accelerate vasculogenic mimicry formation by stimulating tumor cell plasticity, remodeling the extracellular matrix and connecting vasculogenic mimicry channels with host blood vessels. However, strict histoembryological and histopathological definitions classify endothelial cells as a subtype of epithelial cells. In contrast, cancer cells may originate from either epithelial or mesenchymal origins. From the perspective of tumor biology, cancer cell endothelialization represents a specialized form of lineage-directed differentiation, whereby malignant cells of epithelial or mesenchymal origin transition into vascular or lymphatic endothelial cell phenotypes. Mirroring angiogenesis, tumour cells were also shown to secrete lymphangiogenic factors that facilitate lymphangiogenesis and metastasis to sentinel lymph nodes. However, the mechanisms underlying the pathologic growth and function of the lymphatic vascular system have remained poorly understood. Given space constraints, this review primarily examines the concept, background, cellular and molecular mechanisms, molecular markers, histopathological characteristics, clinical significance, and targeted therapeutic approaches related to the lymphatic endothelialization of cancer cells derived from epithelial lineages.
Concept and Background of Cancer Cell Lymphatic Endothelialization
Cancer cell lymphatic endothelialization is one of the two recognized forms of cancer cell endothelialization, alongside cancer cell vascular endothelialization. This process involves the transformation of malignant cells into lymphatic endothelial-like cells during tumor progression, presenting a novel perspective on the origin of tumor neolymphatic endothelial structures within tumors and offering insights into tumor-associated lymphangiogenesis and lymphatic metastasis.1,3,4
Traditional perspectives in developmental cell biology have posited that somatic cell lineage differentiation is typically unidirectional, non-selective, and irreversible. However, recent research indicates that both normal and malignant cells can exhibit significant cellular plasticity in response to specific internal or external factors. This plasticity enables reprogramming toward alternative differentiation pathways and the potential to transform into one or more distinct cell lineages. Notable examples include squamous metaplasia of cervical columnar epithelium during cell injury repair and the presence of glandular differentiation within squamous cell carcinoma tissues. Such lineage transitions may occur through dedifferentiation, wherein cells revert to a less differentiated state within the same lineage, or through transdifferentiation, where differentiation occurs toward a different cell lineage. These processes are accompanied by coordinated molecular, metabolic, morphological, and functional transitions.5,7–11 In some instances, these transformations occur bidirectionally, as observed in epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), as well as reciprocal processes of cancer cell endothelialization and endothelial cell cancerization discussed in this review.1,3,12,13
Cellular and Molecular Mechanisms of Cancer Cell Lymphatic Endothelialization
The cellular mechanisms underlying cancer cell lymphatic endothelialization encompass two primary forms: the transdifferentiation of malignant cells into lymphatic endothelial cells and the fusion of cancer cells with pre-existing lymphatic endothelial cells. Normal endothelial cell nuclei are strictly diploid, whereas tumor-derived endothelial cells undergoing cancer cell endothelialization exhibit polychromosomal aneuploidy.1,2 Cancer cells may directly transdifferentiate into lymphatic endothelial cells, or alternatively, dedifferentiate into mesenchymal stem cells before transdifferentiating into lymphatic endothelial cells. Alternatively, cancer cells may fuse with lymphatic endothelial cells, leading to the formation of aneuploid endothelial cells, multinucleated heterokaryotic clusters, and syncytial structures.14,15 These hybrid cells exhibit features characteristic of both cancer cells and lymphatic endothelial cells. Such phenotypes include the proliferative, migratory, and invasive capabilities typical of malignant cells, as well as behaviors such as sprouting, cord formation, and tubulogenesis.10,16,17 Moreover, tumor-associated fibroblasts, along with immune cells like lymphocytes and macrophages, influence the process of cancer cell lymphatic endothelialization by releasing growth factors, cytokines, inflammatory mediators, and other signaling molecules into the tumor microenvironment.3,18–21
At the molecular level, cancer cell lymphatic endothelialization involves exosome-mediated signaling, transcriptional reprogramming, and the activation of various signaling pathways. Tumor type and individual differences may contribute to varying sensitivity and responsiveness of cancer cells to endothelialization-inducing stimuli. Lymphatic endothelial cells primarily express VEGFR-3 and NRP2, which bind directly or synergistically with the ligands VEGFC-C and VEGF-D, forming key molecular axes that regulate lymphangiogenesis and lymphatic endothelial cell function.22,23 Several signaling pathways contribute to endothelial cell differentiation, proliferation, sprouting, and migration including NOTCH, MAPK, RhoA, CXCL12/CXCR4, WNT, TEL, BMP, LMO2, ETS variant transcription factor 2, and uPAR pathways, with particular emphasis on hypoxia-inducible factor 1 (HIF-1). Additional pathways include MAPK/AKT, RhoA/Rac, PI3K/FAK, Erk1/2, CD44/c-Met, among others.10,18,24–26 The interaction between cancer cell-derived syncytin and its receptor on endothelial cells contributes to both the formation and apoptosis of hybrid endothelial structures formed during cancer cell lymphatic endothelialization.27,28
Molecular Biological Markers of Cancer Cell Lymphatic Endothelialization
In addition to VEGFR-3 and NRP2, several transmembrane proteins, including PDPN, LYVE1, and nuclear transcription factors such as PROX1, SOX18, have been identified as regulators of lymphatic endothelial cell differentiation. These molecules not only distinguish lymphatic endothelial cells from vascular endothelial cells, but also act as molecular markers indicative of cancer cell lymphatic endothelialization.29–32 The expression of LYVE1 marks the onset of lymphatic endothelial cell competence, while the transcription factor PROX1 plays a role in the preferential formation of lymphatic structures. Additionally, the activation of PDPN and NRP2 is associated with the specialization of lymphatic endothelial cells.3,33 PDPN and LYVE1 are expressed in the cell membrane, whereas PROX1 and SOX18 are expressed within the nucleus. These markers are temporally regulated, with PROX1 and SOX18 contributing to early stage lymphangiogenic differentiation and PDPN and LYVE1 being more prominently involved in later stages.34,35 The classification, gene localization, subcellular distribution, and roles of these lymphatic-associated molecules in lymphangiogenesis and lymphatic metastasis are presented in Table 1.
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Table 1 Characteristics and Roles of Lymphatic-Associated Molecules in Lymphangiogenesis and Lymphatic Metastasis
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Recent studies have demonstrated that these lymphatic-associated molecules, including PDPN, LYVE1, PROX1, and SOX18, are also highly expressed in various epithelial and mesenchymal malignancies.36–40 For instance, PDPN is predominantly expressed at the periphery of cancer nests in lung, laryngeal, cervical, skin, and esophageal cancers, and contributes to the formation of filopodia-like membrane protrusions, thereby enhancing matrix penetration in breast cancer cells.41,42 LYVE1 expression is significantly elevated in breast cancer with lymph node metastasis and is also associated with tumor stage, recurrence, and metastasis in head and neck squamous cell carcinoma and gastric cancer.43,44 PROX1 expression is notably elevated in breast and colorectal cancer tissues with lymph node involvement.45 Furthermore, SOX18 expression is upregulated in gastric, ovarian, non-small cell lung, breast, cervical, and squamous cell carcinomas. Functional studies have shown that deletion of the SOX18 gene leads to a reduction in the incidence of lymph node metastasis rate in breast cancer models.46,47
Histopathological Characteristics of Cancer Cell Lymphatic Endothelialization
Previous studies have indicated that tumor cells in human malignant melanoma could mimic vascular endothelial cells to form vascular lumen-like structures containing erythrocytes, a phenomenon termed tumor cell vasculogenic mimicry. This process is recognized as a significant contributor to hematogenous metastasis of tumor cells.16,18,48–50 Owing to the developmental and structural similarities between lymphatic and blood vessels, the occurrence of tumor cell lymphangiogenic mimicry has more recently been identified. In this context, tumor cells mimic lymphatic endothelial cell behavior by forming lymphatic lumen-like structures, which contain lymphatic components rather than red blood cells. This phenomenon provides the structural foundation for the propensity of tumor cells to undergo lymphatic metastasis and represents a key histopathological feature of cancer cell endothelialization.1,4,51–54
Similar to vasculogenic mimicry, lymphangiogenic mimicry consists of three histopathological subtypes, each defined by differences in wall cell composition, pathomorphological manifestations, immunohistochemical profiles, and their relationship with the cancer cell lymphatic endothelialization process, as presented in Table 2.1,53–55 The subtypes—referred to as the lymphatic-like type, mosaic type, and lymphatic type—represent the initial, intermediate transition, and terminal stages of the endothelialization process, respectively. Comprehensive identification and characterization of these mimicry types can be achieved through the use of immunohistochemical markers, pathological histology, and microscopic imaging. These approaches are further enhanced by techniques such as fluorescence in situ immunohybridization, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and next-generation sequencing. These methods facilitate the detection and confirmation of molecular biological markers and histopathological features associated with cancer cell lymphatic endothelialization.56
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Table 2 Types of Lymphangiogenic Mimicry: Wall Cell Composition, Histopathological Features, Immunohistochemical Markers, and Association with Cancer Cell Lymphatic Endothelialization
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Clinical Significance and Targeted Therapy of Cancer Cell Lymphatic Endothelialization
During tumor-associated lymphangiogenesis, the endothelial lining of neolymphatic vessels is thought to originate from three primary sources. The first includes pre-existing normal endothelial cells within the tumor stroma. The second involves bone marrow-derived endothelial progenitor cells. The third and predominant source comprises tumor-derived endothelial cells formed through the process of cancer cell endothelialization. These tumor-derived endothelial cells are in direct contact with lymphatic fluid, facilitating their detachment and migration to regional sentinel lymph nodes. This facilitates the increase in lymphatic and subsequent hematogenous metastasis rates in patients. Enlargement of regional lymph nodes is often the earliest clinical manifestation of tumors.3,25 Screening for tumor-derived endothelial cells with aneuploid characteristics in peripheral blood, along with the detection of lymphatic-associated molecular markers and lymphangiogenic mimicry patterns, can improve the early diagnosis of tumor lymphatic metastasis associated with cancer cell lymphatic endothelialization. This approach provides a valuable tool for prognostic assessment and monitoring treatment efficacy in patients with cancer.1,51
To date, various targeted therapeutic agents and inhibitors have been employed in clinical, preclinical, and experimental research to address tumor neovascularization and lymphangiogenesis. Table 3 summarizes these agents, including their classifications, representative compounds, and mechanisms of action.10,16,25,52,57,58 These therapeutic strategies may be utilized either independently or in combination to block endothelial cell proliferation, inhibit angiogenesis and lymphangiogenesis, reduce the likelihood of invasion and metastasis, and minimize side effects. Moreover, engineered nanoparticles (NPs) have emerged as delivery vehicles in overcoming the intricate physiological structure and immunosuppressive microenvironment by facilitating targeted drug to activate T cells directly or indirectly, which could reduce side effects and increase biocompatibility.
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Table 3 Classification, Representative Drug Inhibitors and Targeted Mechanisms of Some Antitumor Angiogenesis and Lymphangiogenesis Drugs
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Conclusion
In conclusion, cancer cell lymphatic endothelialization represents a novel biological paradigm that offers a unified explanation for the directed transformation of diverse tumor cell types into lymphatic endothelial-like cells. This framework provides a new theoretical basis for understanding the cellular origin of tumor-associated neolymphatic vasculature and introduces new pathways for investigating mechanisms of tumor lymphangiogenesis and metastasis (Figure 1). Of course, due to the existence of tumor heterogeneity, the lymphatic endothelialization ability of cancer cells from different tissues may also vary. Moreover, different tumor cells can have complex and profound impacts on targeted drug therapy, which are reflected in the diversity of treatment responses, the spatial heterogeneity of target expression, the dynamic compensation of signaling pathways, and the influence on the tumor microenvironment, etc. Therefore, on the basis of in-depth research on the mechanism of the occurrence and development of cancer cell lymphatic endothelialization and a comprehensive understanding of its molecular biological and histopathological characteristics and rules, further exploring the in-depth development and application of more precise and effective targeted drugs for cancer cell lymphatic endothelialization for different specific tissue origin tumor types should be the key focus of the next step.
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Figure 1 Lymphatic endothelialization of cancer cells and tumor lymphangiogenesis and lymphatic metastasis. A. Mimic lymphatic vessel type B. Mosaic lymphatic vessel type C. lymphatic vessel type—represent the initial, intermediate transition, and terminal stages of the endothelialization process, respectively.
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Abbreviations
VEGFR-3, Vascular endothelial growth factor receptor-3; NRP2, Neuropilin-2; HIF1, Hypoxia-inducible factor 1; WNT, Wingless / Integrated; MAPK, Mitogen-activated protein kinase; RhoA, Rho kinase A; PDPN, Podoplanin; LYVE1, Lymphatic Vessel Endothelial Hyaluronan Receptor 1; PROX1, prospero homeobox 1; SOX18, Recombinant Sex Determining Region Y Box Protein 18; CXCL12/CXCR4, C-X-C motif chemokine ligand 12/ C-X-C chemokine receptor type 4; TEL, Telomerase; FLT, Fms-like tyrosine kinase; BMP, Bone Morphogenetic Protein; LMO2, Lim domain only 2; RhoA/Rac, Rho kinase A/Ras-related C3 botulinum toxin substrate; PI3K/FAK, Phosphoinositide 3-kinase / Focal Adhesion Kinase; Erk1/2, Extracellular regulated protein kinases ½; CD44/c-Met, Homing cell adhesion molecule/ MNNG HOS Transforming gene; VEGFR, Vascular Endothelial Growth Factor Receptor; EGFR, Epidermal growth factor receptor; FGFR, Fibroblast Growth Factor Receptor; RET, Receptor Tyrosine Kinase; FGFR, Fibroblast Growth Factor Receptor; Ang, Angiopoietin.
Data Sharing Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author, Jianwu Tang.
Ethics Approval and Consent to Participate
This study did not involve human or animal subjects, and thus, no ethical approval was required. The authors confirm that this review was conducted in accordance with the principles of academic integrity and research ethics.
Acknowledgments
We are particularly grateful to all the people who have given us help on our article.
Funding
The National Natural Science Foundation of China (No. 81071725).
Disclosure
The authors declare that they have no competing interests.
References
1. Lin PP. Aneuploid circulating tumor-derived endothelial cell (CTEC): a novel versatile player in tumor neovascularization and cancer metastasis. Cells. 2020;9(6):1539. doi:10.3390/cells9061539
2. Zhang T, Zhang L, Gao Y, et al. Role of aneuploid circulating tumor cells and CD31+ circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC. Mol Oncol. 2021;15(11):2891–2909. doi:10.1002/1878-0261.13092
3. Larionov A, Hammer CM, Fiedler K, Filgueira L. Dynamics of endothelial cell diversity and plasticity in health and disease. Cells. 2024;13(15:1276. doi:10.3390/cells13151276.
4. Mai KT, Truong LD, Ball CG, Olberg B, Lai CK, Purgina B. Lymphatic endothelial cancerization in papillary thyroid carcinoma: hidden evidence of lymphatic invasion. Pathol Int. 2015;65(5):220–230. doi:10.1111/pin.12272
5. Sun B, Zhang D, Zhao N, Zhao X. Epithelial-to-endothelial transition and cancer stem cells: two cornerstones of vasculogenic mimicry in malignant tumors. Oncotarget. 2017;8(18):30502–30510. doi:10.18632/oncotarget.8461
6. Peri S, Biagioni A, Cianchi F, et al. Chemotherapy resistance-associated epithelial to endothelial transition in gastric cancer. J Biol Regul Homeost Agents. 2018;32(4 Suppl. 1):30.
7. Savagner P, Brabletz T, Cheng C, et al. Twenty Years of Epithelial-Mesenchymal Transition: a State of the Field from TEMTIA X. Cells Tissues Organs. 2024;213(4):297–303. doi:10.1159/000536096
8. Keller G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 2005;19(10):1129–1155. doi:10.1101/gad.1303605
9. Kim KY, Jung YW, Sullivan GJ, Chung L, Park IH. Cellular reprogramming: a novel tool for investigating autism spectrum disorders. Trends Mol Med. 2012;18(8):463–471. doi:10.1016/j.molmed.2012.06.002
10. Pérez-González A, Bévant K, Blanpain C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. Nat Cancer. 2023;4(8):1063–1082. doi:10.1038/s43018-023-00595-y
11. Bergert M, Lembo S, Sharma S, et al. Cell surface mechanics gate embryonic stem cell differentiation. Cell Stem Cell. 2021;28(2):209–216.e4. doi:10.1016/j.stem.2020.10.017
12. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84. doi:10.1038/s41580-018-0080-4
13. Yang D, Guo P, He T, Powell CA. Role of endothelial cells in tumor microenvironment. Clin Transl Med. 2021;11(6):e450. doi:10.1002/ctm2.450
14. García-Silva S, Benito-Martín A, Nogués L, et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat Cancer. 2021;2(12):1387–1405. doi:10.1038/s43018-021-00272-y
15. Ji S, Wu W, Jiang Q. Crosstalk between endothelial cells and tumor cells: a new era in prostate cancer progression. Int J Mol Sci. 2023;24(23:16893. doi:10.3390/ijms242316893.
16. Ge H, Luo H. Overview of advances in vasculogenic mimicry – a potential target for tumor therapy. Cancer Manag Res. 2018;10:2429–2437. doi:10.2147/CMAR.S164675
17. Pang L, Sun Q, Wang W, et al. A novel gene signature for predicting outcome in colorectal cancer patients based on tumor cell-endothelial cell interaction via single-cell sequencing and machine learning. Heliyon. 2025;11(3):e42237. doi:10.1016/j.heliyon.2025.e42237
18. Wei X, Chen Y, Jiang X, et al. Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironment. Mol Cancer. 2021;20(1):7. doi:10.1186/s12943-020-01288-1
19. Karakousi T, Mudianto T, Lund AW. Lymphatic vessels in the age of cancer immunotherapy. Nat Rev Cancer. 2024;24(6):363–381. doi:10.1038/s41568-024-00681-y
20. Wei WF, Zhou HL, Chen PY, et al. Cancer-associated fibroblast-derived PAI-1 promotes lymphatic metastasis via the induction of EndoMT in lymphatic endothelial cells. J Exp Clin Cancer Res. 2023;42(1):160. doi:10.1186/s13046-023-02714-0
21. Choi H, Moon A. Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention [published correction appears in Arch Pharm Res 2018;41(9):941. doi: 10.1007/s12272-018-1071-x.]. Arch Pharm Res. 2018;41(7):711–724. doi:10.1007/s12272-018-1051-1
22. Wang J, Huang Y, Zhang J, et al. Pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis in tumor lymphangiogenesis and lymphatic metastasis. Clin Chim Acta. 2016;461:165–171. doi:10.1016/j.cca.2016.08.008
23. Wang J, Huang Y, Zhang J, et al. NRP-2 in tumor lymphangiogenesis and lymphatic metastasis. Cancer Lett. 2018;418:176–184. doi:10.1016/j.canlet.2018.01.040
24. Liang J, Wang S, Zhang G, He B, Bie Q, Zhang B. A new antitumor direction: tumor-specific endothelial cells. Front Oncol. 2021;11:756334. doi:10.3389/fonc.2021.756334
25. Hendrix MJ, Seftor EA, Seftor RE, Chao JT, Chien DS, Chu YW. Tumor cell vascular mimicry: novel targeting opportunity in melanoma. Pharmacol Ther. 2016;159:83–92. doi:10.1016/j.pharmthera.2016.01.006
26. Aird WC. Molecular heterogeneity of tumor endothelium. Cell Tissue Res. 2009;335(1):271–281. doi:10.1007/s00441-008-0672-y
27. Bjerregaard B, Holck S, Christensen IJ, Larsson LI. Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci. 2006;63(16):1906–1911. doi:10.1007/s00018-006-6201-9
28. Sieler M, Dittmar T. Cell fusion and syncytia formation in cancer. Results Probl Cell Differ. 2024;71:433–465. doi:10.1007/978-3-031-37936-9_20
29. Fujimoto K, Hashimoto D, Kim SW, et al. Novel erectile analyses revealed augmentable penile Lyve-1, the lymphatic marker. Expression Reprod Med Biol. 2024;23(1):e12570. doi:10.1002/rmb2.12570
30. Panara V, Yu H, Peng D, et al. Multiple cis-regulatory elements control prox1a expression in distinct lymphatic vascular beds. Development. 2024;151(9):dev202525. doi:10.1242/dev.202525
31. Meng H, Zhao Y, Li Y, et al. Evidence for developmental vascular-associated necroptosis and its contribution to venous-lymphatic endothelial differentiation. Front Cell Dev Biol. 2023;11:1229788. doi:10.3389/fcell.2023.1229788
32. Huang Y, Lu M, Wang Y, Zhang C, Cao Y, Zhang X. Podoplanin: a potential therapeutic target for thrombotic diseases. Front Neurol. 2023;14:1118843. doi:10.3389/fneur.2023.1118843
33. Sha M, Shen C, Jeong S, et al. Novel discovery of PDPN-positive CAFs contributing to tumor-associated lymphangiogenesis through mesenchymal to lymphatic endothelial transition in intrahepatic cholangiocarcinoma. Genes Dis. 2023;10(6):2226–2228. doi:10.1016/j.gendis.2023.02.023
34. Srinivasan RS, Geng X, Yang Y, et al. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 2010;24(7):696–707. doi:10.1101/gad.1859310
35. Yang Y, Li Y, Li XB, et al. EGR1 enhances lymphangiogenesis via SOX18-mediated activation of JAK2/STAT3 pathway [retracted in]. Comput Math Methods Med. 2023:9796376. doi:10.1155/2023/9796376.].
36. Johnson LA, Banerji S, Lawrance W, et al. Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1. Nat Immunol. 2017;18(7):762–770. doi:10.1038/ni.3750
37. François M, Caprini A, Hosking B, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456(7222):643–647. doi:10.1038/nature07391
38. Ugorski M, Dziegiel P, Suchanski J. Podoplanin – a small glycoprotein with many faces. Am J Cancer Res. 2016;6(2):370–386. doi:.
39. Higashijima Y, Kanki Y. Molecular mechanistic insights: the emerging role of SOXF transcription factors in tumorigenesis and development. Semin Cancer Biol. 2020;67(Pt 1):39–48. doi:10.1016/j.semcancer.2019.09.008
40. Al-Rawi MA, Mansel RE, Jiang WG. Lymphangiogenesis and its role in cancer. Histol Histopathol. 2005;20(1):283–298. doi:10.14670/HH-20.283
41. Bieniasz-Krzywiec P, Martín-Pérez R, Ehling M, et al. Podoplanin-expressing macrophages promote lymphangiogenesis and lymphoinvasion in breast cancer. Cell Metab. 2019;30(5):917–936.e10. doi:10.1016/j.cmet.2019.07.015
42. Sasano T, Gonzalez-Delgado R, Muñoz NM, et al. Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer. J Thromb Haemost. 2022;20(1):104–114. doi:10.1111/jth.15544
43. Karinen S, Hujanen R, Salo T, Salem A. The prognostic influence of lymphatic endothelium-specific hyaluronan receptor 1 in cancer: a systematic review. Cancer Sci. 2022;113(1):17–27. doi:10.1111/cas.15199
44. Anstee JE, Feehan KT, Opzoomer JW, et al. LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer. Dev Cell. 2023;58(17):1548–1561.e10. doi:10.1016/j.devcel.2023.06.006
45. Zhu L, Tian Q, Gao H, et al. PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK. Int J Biol Sci. 2022;18(5):2032–2046. doi:10.7150/ijbs.68960
46. Chen J, Dang Y, Feng W, et al. SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7. Oncogene. 2020;39(33):5536–5552.
47. Grimm D, Bauer J, Wise P, et al. The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol. 2020;67(Pt 1):122–153. doi:10.1016/j.semcancer.2019.03.004
48. Marques Dos Reis E, Vieira Berti F. Vasculogenic mimicry-an overview. Methods Mol Biol. 2022;2514:3–13. doi:10.1007/978-1-0716-2403-6_1
49. Lapkina EZ, Esimbekova AR, Ruksha TG. Vaskulogennaya mimikriya [Vasculogenic mimicry]. Arkh Patol. 2023;85(6):62–69. doi:10.17116/patol20238506162
50. Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol. 2000;156(2):361–381. doi:10.1016/S0002-9440(10)64739-6
51. Zhang J, Hong Y, Wang L, et al. Aneuploid subtypes of circulating tumor cells and circulating tumor-derived endothelial cells predict the overall survival of advanced lung cancer. Front Oncol. 2023;13:829054. doi:10.3389/fonc.2023.829054
52. Chen Y, Jing Z, Luo C, et al. Vasculogenic mimicry-potential target for glioblastoma therapy: an in vitro and in vivo study. Med Oncol. 2012;29(1):324–331. doi:10.1007/s12032-010-9765-z
53. Barsky SH, Shott R, Jones S, et al. The metastatic dichotomy between carcinomas and sarcomas is explained by differential lymphovasculogenic mimicry. FASEB J. 2008;22.
54. Wang QS, He R, Yang F, et al. FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway. Cancer Lett. 2018;420:116–126. doi:10.1016/j.canlet.2018.01.069
55. Silvestri VL, Henriet E, Linville RM, Wong AD, Searson PC, Ewald AJ. A tissue-engineered 3d microvessel model reveals the dynamics of mosaic vessel formation in breast cancer. Cancer Res. 2020;80(19):4288–4301. doi:10.1158/0008-5472.CAN-19-1564
56. Sphyris N, King C, Hoar J, et al. Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth. Oncotarget. 2021;12(8):823–844. doi:10.18632/oncotarget.27940
57. Mi J, Yang F, Liu J, et al. Case report: post-therapeutic laryngeal carcinoma patient possessing a high ratio of aneuploid CTECs to CTCs rapidly developed de novo malignancy in pancreas. Front Oncol. 2022;12:981907. doi:10.3389/fonc.2022.981907
58. Inoue J, Inazawa J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet. 2021;66(9):937–945. doi:10.1038/s10038-021-00938-6
59. Chitoran E, Rotaru V, Stefan DC, Gullo G, Simion L. Blocking tumoral angiogenesis VEGF/VEGFR pathway: bevacizumab-20 years of therapeutic success and controversy. Cancers (Basel). 2025;17(7):1126. doi:10.3390/cancers17071126
60. Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther. 2020;5(1):146. doi:10.1038/s41392-020-00264-x
61. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5(1:22. doi:10.1038/s41392-020-0116-z.
62. Xiong Y, Wang Y, Yang T, Luo Y, Xu S, Li L. Receptor tyrosine kinase: still an interesting target to inhibit the proliferation of vascular smooth muscle cells. Am J Cardiovasc Drugs. 2023;23(5):497–518. doi:10.1007/s40256-023-00596-3
63. Unnisa A, Chettupalli AK, Hussain T, Kamal MA. Recent advances in epidermal growth factor receptor inhibitors (EGFRIs) and their role in the treatment of cancer: a review. Anticancer Agents Med Chem. 2022;22(20):3370–3381. doi:10.2174/1871520622666220408090541
64. Mosalem O, Sonbol MB, Halfdanarson TR, Starr JS. Tyrosine kinase inhibitors and immunotherapy updates in neuroendocrine neoplasms. Best Pract Res Clin Endocrinol Metab. 2023;37(5):101796. doi:10.1016/j.beem.2023.101796
65. Méndez-Valdés G, Gómez-Hevia F, Lillo-Moya J, et al. Endostatin and cancer therapy: a novel potential alternative to anti-VEGF monoclonal antibodies. Biomedicines. 2023;11(3):718. doi:10.3390/biomedicines11030718
66. Gangying C. Design, synthesis and activity study of phenylpiperazine integrin αvβ3 receptor antagonists. Huazhong Univ Sci Technol. 2009. doi:10.7666/d.d
67. Goradel NH, Mohammadi N, Haghi-Aminjan H, Farhood B, Negahdari B, Sahebkar A. Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol. 2019;234(2):1099–1110. doi:10.1002/jcp.27051
68. Xiaomin B, Liwen L, Liang X, et al. The research progress of miRNAs associated with tumor angiogenesis. J Shandong Med. 2020;60(1):3.
69. Xu S, Zhao N, Hui L, et al. MicroRNA-124-3p inhibits the growth and metastasis of nasopharyngeal carcinoma cells by targeting STAT3. Oncol Rep. 2015. doi:10.3892/or.2015.4524
70. Mu L, Guan B, Tian J, et al. MicroRNA-218 inhibits tumor angiogenesis of human renal cell carcinoma by targeting GAB2. Oncol Rep. 2020;44(5):1961–1970. doi:10.3892/or.2020.7759
71. Xue X, Liu Y, Qu L, et al. Ginsenoside Rh3 inhibits lung cancer metastasis by targeting extracellular signal-regulated kinase: a network pharmacology study. Pharmaceuticals. 2022;15(6):758. doi:10.3390/ph15060758
72. Qian ZM, Chen YJ, Bao YX. Pharmacological mechanisms of norcantharidin against hepatocellular carcinoma. Am J Cancer Res. 2023;13(11):5024–5038. doi:.
73. Yang S, Wu S, Dai W, et al. Tetramethylpyrazine: a review of its antitumor potential and mechanisms. Front Pharmacol. 2021;12:764331. doi:10.3389/fphar.2021.764331
74. Kaps L, Klefenz A, Traenckner H, et al. A new synthetic curcuminoid displays antitumor activities in metastasized melanoma. Cells. 2023;12(22):2619. doi:10.3390/cells12222619