유방암 줄기세포 개념 및 제한점

김종빈,안정신,임우성,문병인,Kim, Jong Bin,An, Jeong Shin,Lim, Woosung,Moon, Byung-In 제주대학교 의과학연구소 2018 The Journal of Medicine and Life Science Vol.15 No.2

Cancer, a leading mortality disease following cardiovascular disease worldwide, has high incidence as one out of every four adults in Korea. It was known to be caused by several reasons including somatic mutation, activation of oncogene and chromosome aneuploidy. Cancer cells show a faster growth rate and have metastatic and heterogeneous cell populations compared to normal cells. Cancer stem cells, the most invested field in cancer biology, is a theory to explain heterogeneous cell populations of cancer cells among several characteristics of cancer cells, which is providing the theoretical background for incidence of cancer and treatment failure by drug resistance. Cancer stem cells initially explain heterogeneous cell populations of cancer cells based on the same markers of normal stem cells in cancer, in which only cancer stem cells showed heterogeneity of cancer cells and tumor initiating ability of leukemia. Based on these results, cancer stem cells were reported in various solid cancers such as breast cancer, liver cancer, and lung cancer. Breast cancer stem cells were first reported in solid cancer which had tumor initiating ability and further identified as anti-cancer drug resistance. There were several identification methods in breast cancer stem cells such as specific surface markers and culture methods. The discovery of cancer stem cells not only explains heterogeneity of cancer cells, but it also provides theoretical background for targeting cancer stem cells to complete elimination of cancer cells. Many institutes have been developing new anticancer drugs targeting cancer stem cells, but there have not been noticeable results yet. Many researchers also reported a necessity for improvement of current concepts and methods of research on cancer stem cells. Herein, we discuss the limitations and the perspectives of breast cancer stem cells based on the current concept and history.

Comparison of CD133 and ABCG2 Expression in Cancer Stem Cells

JaYoungKim,EunKyungAhn,SeunJaPark,YoungHoKim,SunHeeLeem,JeonghoonHeo 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.5

Cancer stem cells in various tumors have been isolated by antigenic markers on cell surface or functional markers for cancer stem cells. The purpose of this study is explore if the expression of CD133, known as surface marker for common cancer stem cells, is related to the expression of ABCG2, known as the functional marker for stem cells in various cancer cell lines. We determined the expression of CD133 and ABCG2 in the established human gastric cancer cell line (SNU216), hepatoblastoma cell line (HepG2), colon cancer cell line (SNU1040), and brain tumor cell line (A172). SNU 216 and SNU 1040 cells showed a higher level of CD133 expression, whereas HepG2 and A172 cells expressed almost undetectable level of CD133. However the expression level of ABCG2 was higher in HepG2 and A172 cells than in SNU 216 and SNU 1040 cells. 5-FU treatment increased both of the CD133 and ABCG2 expression in SNU216 and SNU1040 cells, but not in HepG2 and A172. The expression of ABCG2 in CD133 positive population of SNU1040 and A172 cells was higher than in CD133 negative population. This study showed there is a relationship between CD133 and ABCG2 expression in some cancer cell lines but not in all. CD133 positive cells expressing ABCG2 in a high level may be more resistant to anti-cancer drug, which suggest that CD133 might be a useful marker to isolate cancer stem cells having a resistance to anti-cancer-drug.

Functionalizing Liposomes with Dual Aptamers for Targeting of Breast Cancer Cells and Cancer Stem Cells

Hee-Bin Park,Ji-Eun You,Pyung-Hwan Kim,Keun-Sik Kim 대한의생명과학회 2021 Biomedical Science Letters Vol.27 No.1

Cancer stem cells, which are known to drive tumor formation and maintenance, are a major obstacle in the effective treatment of various types of cancer. Trans-membrane glycoprotein mucin 1 antigen and cell surface glycogen CD44 antigen are well-known surface markers of breast cancer cells and breast cancer stem cells, respectively. To effectively treat cancer cells and cancer stem cells, we developed a new drug-encapsulating liposome conjugated with dual-DNA aptamers specific to the surface markers of breast cancer cells and their cancer stem cells. These two aptamer (Apt)-targeted liposomes, which were prepared to encapsulate doxorubicin (Dox), were named "Dual-Apt-Dox". Dual-Apt-Dox is significantly more cytotoxic to both cancer stem cells and cancer cells compared to liposomes lacking the aptamers. Furthermore, we demonstrated the inhibitory efficacy of Dual-Apt-Dox against the experimental lung metastasis of breast cancer stem cells and cancer cells in athymic nude mice. We also showed the potent antitumor effects of dualaptamer-conjugated liposome systems by targeting cancer cells as well as cancer stem cells. Thus, our data indicate that dual-aptamer-conjugated liposome systems can prove to be effective drug delivery vehicles for breast cancer therapy.

구강 편평세포암종에서의 암줄기세포 이론과 최신 지견

김덕훈(Deok-Hun Kim),윤준용(Jun-Yong Yun),이주현(Ju-Hyun Lee),김성민(Soung-Min Kim),명 훈(Hoon Myoung) 대한구강악안면외과학회 2011 대한구강악안면외과학회지 Vol.37 No.2

Cancer stem cells have stem cell-like features, such as the ability for self-renewal and differentiation but show unlimited growth because they have the lost normal regulation of cell growth. Cancer stem cells and normal stem cells have similar features. They show high motility, diversity of progeny, robust proliferative potential, association with blood vessels, immature expression profiles, nestin expression, epidermal growth factor (EGF)-receptor expression, phosphatase and tensin homolog (PTEN) expression, hedgehog pathway activity, telomerase activity, and Wnt pathway activity. On the other hand, with cancer cells, some of these signaling pathways are abnormally modified. In 1875, Cohnheim suggested the concept of cancer stem cells. Recently, evidence for the existence of cancer stem cells was identified. In 1994, the cancer stem cells’specific cell surface marker for leukemia was identified. Since then, other specific cell surface markers for cancer stem cells in solid tumors (e.g. breast and colon cancer) have been identified. In oral cancer, studies on cancer stem cells have been performed mainly with squamous cell carcinomas. Oral cancer specific cell surface markers, which are genes strongly expressed in oral cancer and cancer stem cell specific side populations, have been identified. Cancer stem cells are resistant to radiotherapy and chemotherapy. Therefore, to eliminate malignant tumors efficiently and reduce the recurrence rate, therapy targeting cancer stem cells needs to be performed. Currently, studies targeting the cancer stem cells’specific signaling pathways, telomerase and tumor vasculatures are being done.

Liver Cancer Stem Cell Induction from Induced Pluripotent Stem Cells

( Said M Afify ),( Ghmkin Hassan ),( Hend M Nawara ),( Hager M Mansour ),( Amira Osman ),( Sadia Monzur ),( Hagar Ali Abu Quora ),( Maram H Zahra ),( Akimasa Seno ),( Yoshiaki Iwasaki ),( Masaharu Sen 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Liver cancer stem cells represent a small fraction of cells in liver cancer tissues so that studying these cells is very hard. Generation of liver cancer stem cells considered as one of the most important issue in cancer biology research. For this reason, we tried to generate liver cancer stem cells from induced pluripotent stem (iPSCs). Methods: First of all, CM was collected from confluent culture of Huh7 cells. Then, mouse iPSCs cells without MEF feeder cells were cultured in the presence of 50% CM for 4 weeks. The medium was changed every day with fresh medium containing 50% of CM. Mouse iPSCs cultured is the complete medium with LIF were used as a control. The survived cells (5x105 cells) were suspended in HBSS and injected into the liver of BALB/ c nude mice. After 25 days malignant tumor was formed in the liver while benign teratoma was formed by the injection of iPSCs. Tumors were then excised and partly fixed in 10% neutral formalin buffer solution for HE staining and immunohistochemical analysis. The rest of tumors were subjected to rt-qPCR anaylsis and primary culture. Results: Immunohistochemical analysis with liver cancer associated markers and cancer stem cell marker showed that malignant liver tumor was developed. These results indicate that the primary cells from the malignant tumor are rich in CSCs. Conclusions: This model will be very important and useful to assess the significant molecular mechanisms necessary to maintain liver cancer stem cells, which will help in defat liver cancer.

Interleukin‐32 enhances cytotoxic effect of natural killer cells to cancer cells via activation of death receptor 3

Park, Mi H.,Song, Min J.,Cho, Min‐,Chul,Moon, Dong C.,Yoon, Do Y.,Han, Sang B.,Hong, Jin T. Blackwell Publishing Ltd 2012 Immunology Vol.135 No.1

<P><B>Summary</B></P><P>Studies have demonstrated that the anti‐tumour effect of natural killer (NK) cells is successful for patients with several cancers. Although interleukin‐32 (IL‐32) is endogenously expressed in NK cells, cytolytic function of NK cells against cancer cells has not been fully demonstrated. In the present study, we found that the growth of cancer cells was suppressed when colon cancer cells or prostate cancer cells were co‐cultured with NK‐92 cells, an NK cell line. We also found that the expression of tumour necrosis factor receptor 2 and death receptor 3 (DR3) was increased in PC3 cells, and the expression of FAS and DR3 was increased in SW620 cells by co‐culture with NK‐92 cells. However, cancer cell growth inhibition and IL‐32 expression were abolished when cancer cells were co‐cultured with NK cells transfected with small interfering (si) RNA of IL‐32. DR3 expression was also diminished by co‐culture with IL‐32‐specific siRNA‐transfected NK‐92 cells. Expression of APO3L, a ligand of DR3, was elevated in NK cells that were co‐cultured with cancer cells. It was also found that expression of apoptosis‐related proteins such as cleaved caspase‐3 and bax was increased in cancer cells co‐cultured with NK‐92 cells, but their expression was abolished by co‐culture with IL‐32 siRNA‐transfected NK‐92 cells. Moreover, knockdown of DR3 in co‐culture of NK‐92 cells with cancer cells by siRNA or antibodies of DR3 and APO3L reversed the growth inhibitory effect of NK‐92 cells. In conclusion, our study showed that IL‐32 enhanced the cytotoxic effect of NK‐92 cells on the cancer cells through activation of DR3 and caspase‐3.</P>

Growth inhibition by metformin in YD-38 oral cancer cells derived from Korean

( Dong Kuk Seo ),( Su-gwan Kim ),( Dae-san Go ),( Chun Sung Kim ),( Sun-kyoung Yu ),( Do Kyung Kim ) 조선대학교 구강생물학연구소 2017 Oral Biology Research (Oral Biol Res) Vol.41 No.2

Metformin (1,1-dimethylbiguanide hydrochloride), derived from French lilac (Galega officinalis), is a first-line drug prescribed for patients with type 2 diabetes. It has been reported to have anti-cancer effects in a variety of cancer cells. However, effects of metformin on oral cancer cells have not been clearly established. The main goal of this study was to investigate the effect of metformin on cell growth and apoptosis induction in oral cancer cells derived from Korean patients. The effect of metformin on cell growth and apoptosis induction in oral cancer cells was examined by inhibition of cell growth, DNA fragmentation analysis and immunoblotting in YD-38 human oral cancer cells derived from Korean patients. Treatment with metformin induced inhibition of cell growth depending on the metformin treatment time and concentration in YD-38 human oral cancer cells. Treatment with metformin induced nuclear fragmentation in YD-38 human oral cancer cells. Metformin promoted proteolytic cleavage of procaspase-3 with an increase in the amount of cleaved caspase-3. Cleaved PARP was increased by metformin in YD-38 human oral cancer cells. Treatment of YD-38 human oral cancer cells with metformin increased the level of Bax, but it decreased the level of Bcl-2. These results suggest that metformin can induce suppression of cell growth and cell apoptosis in YD-38 human oral cancer cells derived from Korean patients.

Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids

Lee, Minji,Song, Yeonhwa,Choi, Inhee,Lee, Su-Yeon,Kim, Sanghwa,Kim, Se-Hyuk,Kim, Jiho,Seo, Haeng Ran Korean Society for Molecular and Cellular Biology 2021 Molecules and cells Vol.44 No.1

Among all cancer types, lung cancer ranks highest worldwide in terms of both incidence and mortality. The crosstalk between lung cancer cells and their tumor microenvironment (TME) has begun to emerge as the "Achilles heel" of the disease and thus constitutes an attractive target for anticancer therapy. We previously revealed that crosstalk between lung cancer cells and endothelial cells (ECs) induces chemoresistance in multicellular tumor spheroids (MCTSs). In this study, we demonstrated that factors secreted in response to crosstalk between ECs and lung cancer cells play pivotal roles in the development of chemoresistance in lung cancer spheroids. We subsequently determined that the expression of hypoxia up-regulated protein 1 (HYOU1) in lung cancer spheroids was increased by factors secreted in response to crosstalk between ECs and lung cancer cells. Direct interaction between lung cancer cells and ECs also caused an elevation in the expression of HYOU1 in MCTSs. Inhibition of HYOU1 expression not only suppressed stemness and malignancy, but also facilitated apoptosis and chemosensitivity in lung cancer MCTSs. Inhibition of HYOU1 expression also significantly increased the expression of interferon signaling components in lung cancer cells. Moreover, the activation of the PI3K/AKT/mTOR pathway was involved in the HYOU1-induced aggression of lung cancer cells. Taken together, our results identify HYOU1, which is induced in response to crosstalk between ECs and lung cancer cells within the TME, as a potential therapeutic target for combating the aggressive behavior of cancer cells.

Metastatic colon cancer cell populations contain more cancer stem-like cells with a higher susceptibility to natural killer cell-mediated lysis compared with primary colon cancer cells

KIM, GA RIM,HA, GA-HEE,BAE, JAE-HO,OH, SAE-OCK,KIM, SUN-HEE,KANG, CHI-DUG D.A. Spandidos 2015 Oncology letters Vol.9 No.4

<P>In the present study, the soft agar clonogenicity and the susceptibility of clonogenic cancer cells to natural killer (NK) cells were compared between primary colon cancer cells (KM12C) and metastatic colon cancer cells (KM12L4a and KM12SM) to determine whether the metastatic cancer cells consisted of more cancer stem-like cells and were resistant to NK cell-mediated lysis. The majority of colon cancer cells were positive for putative cancer stem cell markers, including CD44, CD133 and EpCAM, with the exception of KM12C cells, of which only ~55% were positive for CD133. In addition, the expression levels of sex determining region Y-box 2, Nanog and octamer-binding transcription factor 4, which are essential for maintaining self-renewal, were higher in KM12L4a and KM12SM compared with that in KM12C cells. Consistently, an increased clonogenicity of KM12L4a and KM12SM compared with KM12C cells in soft agar was observed. The expression levels of NKG2D ligands, including major histocompatibility complex class I polypeptide-related sequence A/B and UL16 binding protein 2, and of death receptor 5 were significantly higher in KM12L4a and KM12SM than in KM12C cells. Furthermore, the results indicated an increased susceptibility of KM12L4a and KM12SM to NK cell-mediated cytotoxicity in comparison with KM12C cells. These results indicated that metastatic colon cancer cell populations may consist of more cancer stem-like cells, and have greater susceptibility to NK cell-mediated lysis compared with that of primary colon cancers.</P>

황련해독탕이 수종의 인간 암세포 증식에 미치는 영향

성현경,민상연,김장현,Sung, Hyun Kyung,Min, Sang Yeon,Kim, Jang Hyun 대한한방소아과학회 2013 대한한방소아과학회지 Vol.27 No.1

Objectives The aim of this study is to investigate whether hwang-ryun-haedok-tang (HDT) affect proliferations of androgen-dependent LNCaP prostate cancer cells, androgen-independent PC-3, DU-145 prostate cancer cells, MCF-7 human breast cancer cells, A549, NCI-H292 human pulmonary cancer cells and K-562 human chronic myelogenous leukemia cells. Materials and Methods Effects of HDT on proliferations of each cancer cell line were investigated. 20,000 cells/well were plated in each well of 96-well culture plate. After 24 hrs, 0.01-10% of HDT in culture medium was added to cancer cells. The number of cells was counted by using SRB assay or direct cell counting method after 72 hours from drug treatment. Effect of baicalein or berebrine on proliferation was assessed according to the same method. Results (1) HDT inhibited proliferations of LNCaP, PC-3 and DU-145 prostate cancer cells. (2) HDT inhibited proliferation of MCF-7 breast cancer cells. (3) HDT also inhibited proliferations of A549, NCI-H292 pulmonary cancer cells and K-562 chronic myelogenous leukemia cells. (4) Baicalein and berberine also showed inhibitory effects on proliferations of prostate and breast cancer cells. Conclusion : HDT inhibited proliferations of human prostate, breast, pulmonary and blood cancer cells. These results suggest us the potential use of HDT as a chemopreventive or chemotherapeutic agent. Effect of HDT on human cancer should be further investigated using in vivo experimental models that can reflect pathophysiology of human cancer through another studies.