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Metastasis Model of Cancer Stem Cell-Derived Tumors

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Metastasis Model of Cancer Stem Cell-Derived Tumors Protocol Metastasis Model of Cancer Stem Cell-Derived Tumors Hager Mansour 1, Ghmkin Hassan 2,3 , Said M. Afify 2,4 , Ting Yan 5, Akimasa Seno 1,2 and Masaharu Seno 1,2,* 1 Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan; [email protected] (H.M.); [email protected] (A.S.) 2 Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan; [email protected] (G.H.); saidafi[email protected] (S.M.A.) 3 Department of Microbiology and Biochemistry, Faculty of Pharmacy, Damascus University, Damascus 10769, Syria 4 Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin El Koum-Menoufia 32511, Egypt 5 Department of Pathology, Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan 030001, China; [email protected] * Correspondence: [email protected] Received: 21 July 2020; Accepted: 17 August 2020; Published: 21 August 2020 Abstract: Metastasis includes the dissemination of cancer cells from a malignant tumor and seed in distant sites inside the body forming secondary tumors. Metastatic cells from the primary tumor can move even before the cancer is detected. Therefore, metastases are responsible for more than 90% of cancer-related deaths. Over recent decades there has been adequate evidence suggesting the existence of CSCs with self-renewing and drug-resistant potency within heterogeneous tumors. Cancer stem cells (CSCs) act as a tumor initiating cells and have roles in tumor retrieve and metastasis. Our group recently developed a unique CSC model from mouse induced pluripotent stem cells cultured in the presence of cancer cell-conditioned medium that mimics tumors microenvironment. Using this model, we demonstrated a new method for studying metastasis by intraperitoneal transplantation of tumors and investigate the metastasis ability of cells from these segments. First of all, CSCs were injected subcutaneously in nude mice. The developed malignant tumors were minimized then transplanted into the peritoneal cavity. Following this, the developed tumor in addition to lung, pancreas and liver were then excised and analyzed. Our method showed the metastatic potential of CSCs with the ability of disseminated and moving to blood circulation and seeding in distant organs such as lung and pancreas. This method could provide a good model to study the mechanisms of metastasis according to CSC theory. Keywords: metastasis; cancer stem cells; transplantation; surgery 1. Introduction Metastasis is spreading of cancer to tissues or organs far from their original sites where they originated. Cancer metastasis enables forming secondary tumors in distant organs and is major responsible for the mortality and morbidity of cancer [1]. The metastasis includes several events beginning with dissemination of cancer cells from tumors, invading stroma, intravasation and seeding in secondary sites where they form metastasis [2]. Many genes are changing during these stages changing cell phenotypes. Genes, such as E-cadherin, Methods Protoc. 2020, 3, 60; doi:10.3390/mps3030060 www.mdpi.com/journal/mps Methods Protoc. 2020, 3, 60 2 of 8 slug and twist, contribute to give cancer cells the dissemination and movement ability driving metastasis eventsMethods [3]. Protoc. 2020, 3, x FOR PEER REVIEW 2 of 8 On the other hand, cancer stem cells (CSCs) represent the subpopulation of cancer cells with the abilitycadherin, to dislugfferentiate and twist, into contribute other cell to phenotypes give cancer andcells initiatedthe dissemination tumorigenesis. and movement CSCs were ability proved to havedriving essential metastasis roles events in metastasis [3]. and drug resistance characters of cancer cells. When a small On the other hand, cancer stem cells (CSCs) represent the subpopulation of cancer cells with the number of CSCs are injected into immunocompromised animal model, they can form new tumors [4]. ability to differentiate into other cell phenotypes and initiated tumorigenesis. CSCs were proved to CSCs also express stemness markers, Nanog, Sox2 and Oct3/4, and CSC markers such as EpCAM, have essential roles in metastasis and drug resistance characters of cancer cells. When a small number CD133,of CSCs CD44, are and injected CD24. into CSCs immunocompromised usually enrichment animal from model, either they from can cancer form new cell tumors lines or [4]. from CSCs patient derivedalso samples.express stemness Isolation markers, of CSC Nanog, is still Sox2 considered and Oct3/4, a challenging and CSC markers and demandingsuch as EpCAM, procedure CD133, [5,6]. InducedCD44, pluripotent and CD24. stemCSCs cellsusually (iPSCs) enrichment have opened from either the from door cancer for personalized cell lines or from medicine patient and derived facilitated modelingsamples. a wide Isolation range of ofCSC diseases. is still considered Our lab hasa challenging established and novel demanding CSC models procedure by [5,6]. converting Induced iPSCs into CSCs.pluripotent Conversion stem cells of iPSCs(iPSCs) into have CSCs opened has beenthe door demonstrated for personalized by culturing medicine iPSCs and infacilitated the presence of conditionedmodeling a media wide range (CM) of from diseases. different Our cancerlab has cellestablished lines secreting novel CSC cytokines, models chemokinesby converting and iPSCs growth factorsinto that CSCs. direct Conversion the conversion of iPSCs without into CSCs genetic has been manipulation demonstrated of by iPSCs. culturing Accordingly, iPSCs in the we presence successfully of conditioned media (CM) from different cancer cell lines secreting cytokines, chemokines and established different mouse cell models using CM from lung, breast, pancreas and liver cancer cell growth factors that direct the conversion without genetic manipulation of iPSCs. Accordingly, we lines [7–11]. successfully established different mouse cell models using CM from lung, breast, pancreas and liver Thecancer selection cell lines of[7–11]. the method to investigate the metastasis is critical for the identification and candidateThe genes selection and mechanisms of the method that to may investigate regulate the metastasis metastasis and is critical for the for evaluation the identification of anti-metastatic and drugs.candidate Recent genes methods and includemechanisms detecting that may metastasis regulate aftermetastasis transplantation and for the of evaluation cancer cells of anti- or tissue eithermetastatic orthotopically drugs. Recent or ectopically methods include in addition detecting to themetastasis injection after of transplantation cancer cells inof cancer blood cells circulation or or intraperitoneallytissue either orthotopically [12,13]. However, or ectopically these in methods addition still to dothe notinjection accurately of cancer present cells thein metastasisblood eventscirculation especially or intraperitoneally regarding the disposition [12,13]. However, of cells these from methods original still tumors do not and accurately injections present cancer the cells neglectsmetastasis dissemination events especially step which regarding is main the thedisposition step in theof cells metastasis from original events. tumors Therefore, and injections developing cancer cells neglects dissemination step which is main the step in the metastasis events. Therefore, new methods is becoming important to investigate metastasis and screening new drugs. Our present developing new methods is becoming important to investigate metastasis and screening new drugs. uniqueOur models present unique that enabling models that investigation enabling investigation of tumor of progression tumor progression events events according according to CSCto CSC theory. In thistheory. manner, In this we manner, present we here present a new here method a new for method studying for studying metastasis metastasis using CSC using model CSC model developed fromdeveloped iPSCs. Our from method iPSCs. investigates Our method the investigates ability of CSCsthe ability to disseminate of CSCs to fromdisseminate bulk intraperitoneally from bulk transplantedintraperitoneally tumor andtransplanted metastasis tumor into and secondary metastasis sites. into secondary sites. 2. Experimental2. Experimental Design Design We haveWe have developed developed a protocol a protocol for for tumor tumor tissuetissue tr transplantationansplantation using using cancer cancer stem stem cell developed cell developed tumor.tumor. In our In assay, our weassay, describe we describe step by step evaluatingby step evaluating the model the of metastasismodel of metastasis by tissue transplantationby tissue of CSCtransplantation derived tumor of CSC as summarizedderived tumor in as Figure summariz1. Thised in protocol Figure will1. This be veryprotocol important will be tovery guide important to guide researchers who will follow developing metastasis from CSCs to evaluate researchers who will follow developing metastasis from CSCs to evaluate treatment strategies and treatment strategies and molecular mechanisms of metastasis development from the sight of CSC molecular mechanisms of metastasis development from the sight of CSC theory. The surgical procedure theory. The surgical procedure is performed under sterile conditions. All instruments are sterilized is performedby autoclaving under before
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