To the Editor: It has been eighteen years since telocytes (TCs) were first categorized by Popescu et al[1] in 2005. TCs were classified into interstitial cells of the Cajal (ICC) type based on their ultrastructure and immunohistochemical features, which are similar to mesenchymal cells.[2] In the following ten years, TCs were found to have their own distinctive characteristics in terms of three-dimensional structure, immunological biomarkers, genomics, and multiple functions. Interestingly, TCs are definitely distinct from fibroblasts, mesenchymal stem cells, and endothelial cells in multiple organs of human beings and animals.[3] They possess a particular cell body and a significantly different number of telopodes (Tps), which are considered as characteristic features compared to classical fibroblasts and endothelial cells.[4] Tps form a moniliform pattern, consisting of thin segments (podomers) and small dilated regions (podsoms). The conbination of immunohistochemical biomarker analysis and transmission electron microscopy scanning, along with scanning electron microscopy (SEM) assay has become the “Gold Standard” protocol for distinguishing TCs from other interstitial cells.[5] Under the SEM imaging, TCs with their interconnected Tps display a three-dimensional fabric that constructs an unabridged and convoluted network, indicating their ability to interact with parenchyma cells, immune cells, and cancer cells.[6]

The pivotal infrastructure and stimuli produced by TCs are essential for the survival, proliferation, polarization, maturation, and organ reestablishment processes of surrounding cells in various tissues. In particular, TCs have been identified as an independent risk factor for multiple cancers, including hepatocellular carcinoma (HCC), colorectal cancer, uterine leiomyoma, bladder cancer, breast cancer, and basal cell carcinoma [Supplementary Figure 1, https://links.lww.com/CM9/B899]. Furthermore, TCs are even considered as collaborators in immunological regulation and surveillance.[7] This review summarizes the latest findings and concepts regarding TCs in neoplasms, and presents evidence supporting the classification of “tumor-associated telocytes (TATCs)”.

The tumor microenvironment (TME) is a dynamic environment created by the interaction between cancer cells and the surrounding cells, which contains parenchyma cells, interstitial cells, cytokines, chemokines, extracellular vesicles, and immune cells. Among these cells, TCs were found playing a crucial role in the TME based on their morphology, cellular identification, immunophenotypic heterogeneity, and genomic characteristics.[8] TCs have three main ways of interacting with surrounding cells: direct secretion from TCs body, paracrine from Tps, and extracellular vesicles released from cell membrane channels, demonstrating that TCs contribute to being a pivotal position in transmitting intracellular signaling.[9] In cancer specimens, TCs exhibit gene heterogeneity on specific chromosomes, indicating their diverse effects on tumor cell behavior, such as cell signaling, expansion, movement, tumorigenesis, and inflammatory resistance.[10,11] TCs can be distinguished from other interstitial cell subtypes based on their unique microRNAs, immunohistochemical biomarkers, and immunofluorescent incorporation techniques. Immunohistochemical and immunofluorescent staining for biomarkers such as cluster of differentiation 34 (CD34) and platelet-derived growth factor receptor alpha (PDGFRA) can be used to identify TCs in cancer tissues, while negative expression for CD31 and vimentin helps differentiate TCs from other cell types.[12] However, due to the widespread gene mutations in the TME, TCs may inconsistently express aberrant stem cell markers, necessitating specific biomarkers for different organs and tissues to accurately identify TCs. A significant change is that TCs in the normal vascular wall, which express CD34, have the ability to transform into TCs expressing CD68 and matrix metalloproteinase-9 (MMP9) during tumor angiogenesis and proliferation processes.[13] The pivotal functions of TCs in TME have been reported, and this could potentially provide a strong basis for naming them as TATCs.

When concentrating attention on the ultrastructure and immunological features of TCs in liver tissues, researchers observed that TCs apparently had positive expression for CD34, PDGFR, and CD117 (KIT proto-oncogene, receptor tyrosine kinase), but negative expression for CD28 and vimentin.[14] Analyzing the heterogeneity of TCs between the HCC tissue and para-cancer tissue showed that the quantity of TCs in the para-cancer tissue was signigicantly higher than that in the cancer tissue, and the expression of MMP9 was consistent with the number of TCs. Additionally, evidence has shown that activated TCs could promote the invasion and migration of liver cancer cells through the extracellular signal-regulated kinase (ERK) signaling pathway, leading to increase of the expression of MMP9. Furthermore, TATCs form a three-dimensional space with several Tps in the TME of HCC. It had been confirmed that MHCC97 cells secreted the PDGF into intercellular gaps, which could be specially captured by Tps and initiated a cascade reaction. Moreover, apart from cytokines, extracellular vesicles derived from cancer cells are also considered as components for signal transmission.[15] For example, it has been demonstrated that HCC tumor-derived exosomal long non-coding RNA (LncRNA) SNHG16 down-regulates the expression of miR-942-3p, which is a specific degrading molecule for MMP9 mRNA in TATCs.[16] In conclusion, above mentioned evidence supports the conception of TATCs in HCC.

Gastrointestinal stromal tumors (GISTs) were first described as mesenchymal neoplasms in 1983, and they perform a similar immunological and morphological features of the ICC, which is homologous to the characteristics of TCs.[17] The source of TCs in GISTs was confirmed to originate from primitive hepatic biliary ducts-tree, but have functions within the extrahepatic biliary tree system. TCs were demonstrated to contribute to the gall bladder motility and the pathogenesis of bladder related diseases. In 2018, a PDGFRα-mutation in TCs of GISTs was reported as a genuine pathogenic factor during the neoplasms proliferated and was named “telocytoma”. The researches of morphological and functional changes of TCs in the GIST elucidated that PDGFRA positive TCs were counterparts with tumor cells by constructing a close-knite space. Therefore, hyperplastic TCs, which are involved in the stromal typical proliferation of PDGFRA-mutant syndrome, were confirmed to be collaborators in the neoplastic process. Additionally, a unique-Cre transgenic mouse model verified that Foxl-1 positive TCs were the essential origin of intestinal stem cell niche factors, and Foxl-1+ TCs could be easily observed in the gastrointestinal system.[12,18] It was also discovered that telocyte–phosphatase and tensin homolog (PTEN) signaling is a vital independently protective pathway inhibiting the colonic polyposis proliferation, the PTEN-deficiency signaling in Foxl-1+ TCs was confirmed to accelerate the colonial neoplasia in a mouse model. Those innovative findings will benefit understanding of TATCs in GI cancer.

In the past five years, studies of TCs’ impact on multiple human neoplasms, such as the urothelial bladder carcinoma, uterine leiomyomas, testicular seminoma, lung cancer, and breast cancer, have attracted attention. TCs, with their functional components, “telopodes”, contribute to divergent efficiencies in the distinct tumors, as well as activating different signaling pathways which play pivotal roles in physiological and pathological processes, especially in pathogenic evolution. Using double labelling of immunochemistry and immunofluorescence assays, CD34-positive TCs were broadly found in the invasive breast lobular carcinomas, showing that they appeared to construct a veil around neoplastic places and infiltrated the TME of invasive lobular carcinoma. In addition, TCs also appeared in the adipose tissue in the connective interlobular areas and submammary regions, which was suggested as a predictor for the progression of invasive breast lobular carcinoma. Interestingly, Aleksandrovych et al[19] demonstrated that TCs exhibited less quantities in the hysteromyoma compared to the uterine cervix tissue and the healthy uterine tissue; meanwhile, their ultra-structures were found to be changing with little response to CD34, c-kit, and PDGFRA biomarkers, suspecting that TCs would forfeit immanent functions, which are normally exerted in the normal uterine tissues. Whereas, the quantities and immunological characteristics of TCs around the leiomyoma presented apparent changes compared to them in the tumor tissue, such as negativity for c-kit, while this entertaining finding gave powerful evidence to support the conception of TATCs in uterine leiomyomas.

In addition, TCs were also explored in the para-bladder carcinoma and tumor-free lamina propria, and found that divergent growth subtypes in bladder cancer presented multiple proliferations of TCs, which was used as a predictive marker of demarcation line during tumor resections.[1] What’s more, CD34+ stromal cells/telocytes (CD34+ SC/TCs) influent the pathologic processes of the skin related-carcinoma, such as dermatofibrosarcoma protuberans, sclerotic fibroma, and solitary fibrous tumors. Microscopically, CD34+ SC/TCs and collagen I, which were the main component of solitary fibrous tumors, co-existed in the collagenous stroma, suggesting that TCs performed a pivotal role in the process of skin related-cancers. Besides, these particular stromal cells (CD34+ SCs/TCs) were testified to be associated with the neovessel formation in the skin Kaposi sarcoma, which was classified as a sort of distinct viral and immunologically related malignant neoplasm.[21] This valuable finding substantiated that CD34+ SCs/TCs delimited the Kaposi sarcoma margin and non-affected pre-existing blood veins through their elongated Tps. Moreover, CD34+ SCs/TCs were initially observed to establish extensive communications with inflammatory cells that were positively pigmented by CD45, evidencing the conception that TATCs could create a three-dimension interactive network and maintain close-knit inter-associations with intricate signaling information in the TME. Intriguingly, the reason why TCs participated in the etiopathogenesis and development of tumors originated from their angiogenesis. A study described an important type of intussusceptive angiogenesis, involving in the functional changes of CD34+ SCs/TCs in the microvasculature. This finding evidence that TCs were detached from a prime perivascular niche by actively altering the surrounding components of matrix and fibrinogen levels, as a result of rearrangements and transformations of sprouting angiogenesis. And, this phenomenon also presented in perivascular neovessles of Kaposi sarcoma, which induced the invasion into circumambient tissues.

In conclusion, TCs can be categorized as TATCs based on four main theories: (1) associated with the prognosis of patients; (2) promoting the migration and invasion of malignant cancers by secreting extracellular matrix metalloproteinase to remodel collagen fiber formation in the TME; (3) reconstructing a three-dimensional network to sustain the plasticity and validity of micro angiogenesis of organic neoplasm; and (4) transforming extensive intercellular signaling information with cytokines, chemokines, and hormonic proteins to the surrounding cells, such as fibroblasts, epithelial cells, immune cells and parenchyma cells. However, the molecular causative mechanism of TATCs is still under bottom. The novel conception of TATCs should be paid sufficient attention in the future.

Funding

This study was supported by found from Shandong Postdoctoral Innovation Project (No. SDCX-ZG-202203046), Natural Science Foundation of Shandong Province (No. ZR2022QH066), and Medical and Health Science and Technology Development of Shandong (No. 202104080599).

Conflicts of interest

None.

References 1. Popescu LM, Gherghiceanu M, Cretoiu D, Radu E. The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells. Electron microscope study in situ. J Cell Mol Med 2005;9:714–730. doi: 10.1111/j.1582-4934.2005.tb00502.x. 2. Liu Y, Fan Y, Wu S. Developments in research on interstitial Cajal-like cells in the biliary tract. Expert Rev Gastroenterol Hepatol 2021;15:159–164. doi: 10.1080/17474124.2021.1823214. 3. Díaz-Flores L, Gutiérrez R, González-Gómez M, García MP, Díaz-Flores L Jr, Carrasco JL, et al. CD34+ Stromal Cells/Telocytes as a Source of Cancer-Associated Fibroblasts (CAFs) in Invasive Lobular Carcinoma of the Breast. Int J Mol Sci 2021;22:3686. doi: 10.3390/ijms22073686. 4. Chen X, Zeng J, Huang Y, Gong M, Ye Y, Zhao H, et al. Telocytes and their structural relationships with surrounding cell types in the skin of silky fowl by immunohistochemistrical, transmission electron microscopical and morphometric analysis. Poult Sci 2021;100:101367. doi: 10.1016/j.psj.2021.101367 5. Chang S, Shen L, Li L, Chen X, Han H. Denoising of scanning electron microscope images for biological ultrastructure enhancement. J Bioinform Comput Biol 2022;20:2250007. doi: 10.1142/S021972002250007X. 6. Ricci R, Giustiniani MC, Gessi M, Lanza P, Castri F, Biondi A, et al. Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA-mutant GISTs. J Cell Mol Med 2018;22:4856–4862. doi: 10.1111/jcmm.13748. 7. Díaz-Flores L, Gutiérrez R, García MP, González-Gómez M, Díaz-Flores L Jr, Carrasco JL, et al. Comparison of the Behavior of Perivascular Cells (Pericytes and CD34+ Stromal Cell/Telocytes) in Sprouting and Intussusceptive Angiogenesis. Int J Mol Sci 2022;23:9010. doi: 10.3390/ijms23169010. 8. Aleksandrovych V, Gil K. Telocytes in the Tumor Microenvironment. Adv Exp Med Biol 2021;1329:205–216. doi: 10.1007/978-3-030-73119-9_11. 9. Smythies J. Intercellular Signaling in Cancer-the SMT and TOFT Hypotheses, Exosomes, Telocytes and Metastases: Is the Messenger in the Message? J Cancer 2015;6:604–609. doi: 10.7150/jca.12372. 10. Luan C, Xu Y. Matrix metalloproteinase gene mutations and bioinformatics of telocytes in hepatocellular carcinoma. Cell Biol Int 2023;47:110–122. doi: 10.1002/cbin.11912. 11. Zhu Y, Zheng M, Song D, Ye L, Wang X. Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes. J Transl Med 2015;13:318. doi: 10.1186/s12967-015-0669-8. 12. Langlois MJ, Servant R, Reyes Nicolás V, Jones C, Roy S, Paquet M, et al. Loss of PTEN Signaling in Foxl1(+) Mesenchymal Telocytes Initiates Spontaneous Colonic Neoplasia in Mice. Cell Mol Gastroenterol Hepatol 2019;8:530–533.e5. doi: 10.1016/j.jcmgh.2019.05.007. 13. Xu T, Zhang H, Zhu Z. Telocytes and endometriosis. Arch Gynecol Obstet 2023;307:39–49. doi: 10.1007/s00404-022-06634-w. 14. Xu Y, Tian H, Cheng J, Liang S, Li T, Liu J. Immunohistochemical biomarkers and distribution of telocytes in ApoE-/- mice. Cell Biol Int 2019;43:1286–1295. doi: 10.1002/cbin.11128. 15. Xu Y, Tian H, Luan CG, Sun K, Bao PJ, Zhang HY, et al. Telocytes promote hepatocellular carcinoma by activating the ERK signaling pathway and miR-942-3p/MMP9 axis. Cell Death Discov 2021;7:209. doi: 10.1038/s41420-021-00592-z. 16. Xu Y, Luan G, Li Z, Liu Z, Qin G, Chu Y. Tumour-derived exosomal lncRNA SNHG16 induces telocytes to promote metastasis of hepatocellular carcinoma via the miR-942-3p/MMP9 axis. Cell Oncol (Dordr) 2023;46:251–264. doi: 10.1007/s13402-022-00746-w. 17. Hayashi Y, Nguyen V. A narrative review of imatinib-resistant gastrointestinal stromal tumors. Gastrointest Stromal Tumor 2021;4:6. doi: 10.21037/gist-21-10. 18. Kolev HM, Tian Y, Kim MS, Leu NA, Adams-Tzivelekidis S, Lengner CJ, et al. A FoxL1-CreERT-2A-tdTomato Mouse Labels Subepithelial Telocytes. Cell Mol Gastroenterol Hepatol 2021;12:1155–1158.e4. doi: 10.1016/j.jcmgh.2021.05.009. 19. Aleksandrovych V, Kurnik-Łucka M, Bereza T, Białas M, Pasternak A, Cretoiu D, et al. The Autonomic Innervation and Uterine Telocyte Interplay in Leiomyoma Formation. Cell Transplant 2019;28:619–629. doi: 10.1177/0963689719833303. 20. Wishahi M, Hassan S, Hassan M, Badawy M, Hafiz E. Telocytes and ezrin expression in normal-appearing tissues adjacent to urothelial bladder carcinoma as predictors of invasiveness and recurrence. Sci Rep 2023;13:6179. doi: 10.1038/s41598-023-33282-021. 21. Díaz-Flores L, Gutiérrez R, González-Gómez M, García M, Palmas M, Carrasco JL, et al. Delimiting CD34+ Stromal Cells/Telocytes Are Resident Mesenchymal Cells That Participate in Neovessel Formation in Skin Kaposi Sarcoma. Int J Mol Sci 2023;24:3793. doi: 10.3390/ijms24043793.