The dynamics of CSCs and CTCs in a chimera subject: the solid organ transplant recipient who develops a neoplastic lesion

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(1)The dynamics of CSCs and CTCs in a chimera subject: the solid organ transplant recipient who develops a neoplastic lesion Giuseppe Ietto. To cite this version: Giuseppe Ietto. The dynamics of CSCs and CTCs in a chimera subject: the solid organ transplant recipient who develops a neoplastic lesion. 2020. �hal-02957212�. HAL Id: hal-02957212 https://hal.archives-ouvertes.fr/hal-02957212 Preprint submitted on 6 Oct 2020. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) The dynamics of CSCs and CTCs in a chimera subject: the solid organ transplant recipient who develops a neoplastic lesion Abstract Tumor spread is responsible of the prognostic worsening and the poor outcome in the most cases. The traditional pathomechanistic model considers all metastatic cells both detected and under suspicion as the result of spreading from the bulky tumor. According to this model, the cellular phenomena that tumor spread is based on are epithelial-to-mesenchimal transition (EMT) and its counterpart, mesenchimal-to-epithelial transition (MET), necessary for the “landing” tissue seeding. These migrating cells can be detected into the blood and are called circulating tumor cells (CTCs). We hypotheses that in some cases the first bulky lesions may origin from a seeding process of CTCs born elsewhere. If such pathogenesis could be reliable regarding aggressive tumor with basic high metastatic potential for which the bulky derives from an undetected first lesion, it is more difficult to imagine this option for disease from less aggressive to properly benign. Supporting our hypothesis, there are some case series concerning tumor growth on transplanted organs which recipient origin is confirmed. The aims of this project are to test the parental origin of all both benign and malign tumors diagnosed in transplanted patients outside the graft and on the graft The detection of cells from different parental origin into a benign or mildly aggressive tumor may support the CSC model, as a worth and credible model concerning tumorigenesis, alternative or parallel to the traditional clonal evolution model proposed by Nowell in 1976. The results of this project might shed new light on the dynamics of CSCs which could be the bases for sustaining the implementation of 3D organoid systems that recapitulate biological diversity of human tumours and are amenable to pharmacological assays for the development of new and promising targeted therapy..

(3) Background and rationale Tumor spread is responsible of the prognostic worsening and the poor outcome in the most cases. The traditional pathomechanistic model considers all metastatic cells both detected and under suspicion as the result of spreading from the bulky tumor. Inside the tumor mass several cells populations become responsible of the local growth, lymphatic spread, perineural invasion and distant metastasis following dissemination through blood stream and long distance seeding. According to this model, the cellular phenomena that tumor spread is based on are epithelial-to-mesenchimal transition (EMT) and its counterpart, mesenchimal-to-epithelial transition (MET), necessary for the “landing” tissue seeding. These migrating cells can be detected into the blood and are called circulating tumor cells (CTCs). Their detection and dosing demonstrated a prognostic value in some cases, breast tumor for example. Among CTCs stemness traits can be detected in some cases. Stem like cells could be part of EMT-MET process, although more likely play an additional role in disseminating of the disease. We hypotheses that in some cases the first bulky lesions may origin from a seeding process of CTCs born elsewhere. If such pathogenesis could be reliable regarding aggressive tumor with basic high metastatic potential for which the bulky derives from an undetected first lesion, it is more difficult to imagine this option for disease from less aggressive to properly benign. Supporting our hypothesis, there are some case series concerning tumor growth on transplanted organs which recipient origin is confirmed.. Objectives The aims of this project are to test the parental origin of all both benign and malign tumors diagnosed in transplanted patients outside the graft and on the graft; to detect CTCs and CSCs in transplanted patients diagnosed with oncological diseases and, if detected, these cells will be tested concerning their parental origins.To this end we will define the prognostic value of detecting CTCs and CSCs and their best markers on the basis of a systematic review of literature and meta analysis..

(4) Methods We will perform a systematic review of literature on the topics concerning CSCs and CTCs in order to select the most recent markers of CTCs, EMT and stemness, with meta analysis concerning the prognostic value of their detection and title compared with conventional staging. We will carry out a retrospective study on a cohort of transplanted patients in order to ● populate a computerized database that will collect all transplanted patients who developed tumors; ● perform an histopathological re-examination of available surgical specimens with microscopic examination, stemness markers detection, EMT (epithelial mesenchymal transition) markers detection and microsatellite analysis. We will carry out a prospective study on patients that underwent solid organ transplantation which develop both benign and malign tumors. On these patients we will check: ● ● ● ● ●. the parental origin of tumoral cells: donor vs recipient. the presence of CTCs. the presence of CSCs the genetic origin of CTCs: donor vs recipient. origin of CSCs: donor vs recipient.. Expected results According to our hypothesis, CSCs play a pivotal role for the development of a tumor. We expect to detect stemness markers both into the tumors’ specimens and among CTCs. First and foremost, these findings may have an interesting prognostic value of worth if it is brought together with TNM stage and cellular grading. Secondly, according the hypothesis of CSCs as tumor initiating cells, the detection of CSCs of recipient origin into a tumor on the transplanted graft and, on the opposite, CSCs of donor origin into a tumor in a different site in the recipient, may contribute to better understanding the pathomechanism of bulky tumor development and metastatic process. In fact, the detection of cells from different parental origin into a tumor can certifying the role of CSCs as tumor initiating cells and shed light on early and diffuse metastasization manifested by such tumor, responsible of their poor prognosis..

(5) The detection of cells from different parental origin into a benign or mildly aggressive tumor may support the CSC model, as a worth and credible model concerning tumorigenesis, alternative or parallel to the traditional clonal evolution model proposed by Nowell in 1976.. Resources In order to complete this project we have to access transplanted patients records of our institution and of external transplant centres. We require the cooperation of pathology lab for histopathological re-examination and laser microdissection of the specimens; chemical lab for flow cytometry analysis with antibody markers of CTCs, EMT and stemness; genetic lab for microsatellite genotyping; informatic lab for database realization and statistical analysis.. Scientific importance e dissemination of results A better understanding of pathomechanisms of tumorigenesis is fundamental for prognostic categorization of different neoplastic diseases. In addition, the evidence of populations of cells with capability of tumour seeding is of worth for neoplastic risk assessment before solid organ transplantation. In fact, detecting CTCs may be very helpful for fast diagnosis of occult or diagnosed neoplasm, which contraindicate the transplantation. Took together the results of this project might shed new light on the dynamics of CSCs which could be the bases for sustaining the implementation of 3D organoid systems that recapitulate biological diversity of human tumours and are amenable to pharmacological assays for the development of new and promising targeted therapy.. References 1. D E, D K, J W, E S, J C, JE S. Imaging tumor cell movement in vivo. Current protocols in cell biology 2013; Chapter 19. 2. MA N. Epithelial plasticity: a common theme in embryonic and cancer cells. Science (New York, NY) 2013; 342(6159). 3.. MA N, RY H, RA J, JP T. EMT: 2016. Cell 2016; 166(1). .

(6) 4. Kawai H, Tsujigiwa H, Siar CH, et al. Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. Int J Med Sci 2018; 15(12): 1406-14. 5. Pichler R, Heidegger I, Aigner F, et al. De novo Renal Cell Carcinoma in a Kidney Allograft with Focus on Contrast-Enhanced Ultrasound. Urologia Internationalis 2018; 93(3): 364-7. 6. Tayoun T, Faugeroux V, Oulhen M, Aberlenc A, Pawlikowska P, Farace F. CTC-Derived Models: A Window into the Seeding Capacity of Circulating Tumor Cells (CTCs). Cells; 2019. 7. Alix-Panabières C. “Circulating Tumor Cells: Finding Rare Events for a Huge Knowledge of Cancer Dissemination”. Cells; 2020..

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