肿瘤干细胞向不同肿瘤细胞分化的实验研究
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摘要
肿瘤干细胞(cancer stem cells, CSCs)的存在已在某些肿瘤细胞株及原发性肿瘤中得到了证实,但肿瘤干细胞是否具有分化成为不同肿瘤细胞的潜能尚未见报道。因此,研究肿瘤干细胞的多向分化潜能对阐明肿瘤的发生、发展和转移,以及发展一种以肿瘤干细胞为靶点的抗肿瘤治疗都具有重要意义。
目的：研究和证实肿瘤干细胞具有分化成为不同肿瘤细胞的潜能。
方法：从原代人肝癌微血管内皮细胞分离培养过程中获得了一种快速增殖的小细胞(命名为T3A),通过将这些细胞在免疫缺陷小鼠成瘤和单细胞克隆技术筛选出生长最迅速、成瘤能力最强的细胞克隆(命名为T3A-A3)。对T3A-A3性质的鉴定分别应用]RT-PCR分析T3A-A3细胞干细胞相关基因mRNA的水平；应用流式细胞术从蛋白水平检测干细胞相关标志的表达；应用甲基纤维素二次集落形成实验及免疫缺陷小鼠二次成瘤实验评价T3A-A3细胞的自我更新能力；并通过染色体核型分析对T3A-A3细胞进行核型鉴定。通过将细胞接种于NOD/SCID鼠后的成瘤和转移情况评价T3A-A3细胞的成瘤能力。为诱导T3A-A3细胞向不同肿瘤细胞分化,选择人黑色素瘤细胞株(SK-MEL-1)和淋巴瘤细胞株(Daudi),用反复低氧-复氧培养分别活化两种肿瘤细胞,然后收集细胞的培养上清用作诱导分化的肿瘤细胞条件培养基,另将两种肿瘤细胞分别接种免疫缺陷小鼠,将成瘤后的肿瘤组织匀浆处理,用以制备肿瘤组织条件培养基。用黑色素瘤细胞和淋巴瘤细胞制备的细胞及组织条件培养基培养T3A-A3细胞21天后,应用RT-PCR、免疫蛋白印迹(Western-blot).细胞免疫荧光染色和免疫组织化学染色方法检测T3A-A3细胞诱导分化前后黑色素瘤细胞特有蛋白gp100和淋巴瘤细胞特异蛋白CD10的表达情况。
此外，通过免疫组织化学染色检测在人肝癌、巨细胞型胶质母细胞瘤、乳腺癌、胶质肉瘤、食管癌和胃印戒细胞癌,以及正常肝、脑、食道和胃组织切片上T3A单抗阳性细胞的分布情况。
结果：RT-PCR结果显示,T3A-A3细胞表达与干细胞增殖、自我更新相关的基因Notch-1, Bmi-1,β-catenin, Oct-4, SMO;表达经典的干细胞标志性分子CD133, CD34, ABCG2, Nestin, C-kit和SCF；表达可诱导的多潜能干细胞(induced pluripotent stem cells,iPS)相关的转录因子Oct-4, Nanog, Lin28, Klf4, Sox2和C-myc。流式细胞术分析显示,T3A-A3细胞表达经典干细胞标志性分子CD133、Nestin, CD34, CD44, ABCG2和Oct-4；二次集落形成实验及二次成瘤实验阳性。染色体核型分析显示,T3A-A3细胞为多倍体；细胞接种到NOD/SCID鼠皮下后,最低1000个细胞即可成瘤；接种1×106T3A-A3细胞于NOD/SCID鼠肝脏,2个月后在胃、肺、结肠发现肿瘤转移灶。T3A-A3细胞经过黑色素瘤细胞和黑色素瘤组织条件培养基诱导3周后,细胞形态发生明显变化,RT-PCR、Western-blot、细胞免疫荧光染色和免疫组织化学染色显示,T3A-A3细胞表达黑色素瘤细胞的特异标志gp100的mRNA和蛋白,表明T3A-A3向黑色素瘤细胞分化；T3A-A3细胞经过淋巴瘤细胞和淋巴瘤组织条件培养基诱导3周后,细胞形态也发生明显变化,RT-PCR、Western-blot、细胞免疫荧光染色和免疫组织化学染色显示,T3A-A3细胞表达淋巴瘤细胞的特异标志CD10的mRNA和蛋白,表明T3A-A3具有向淋巴瘤细胞分化的潜能。通过免疫组织化学染色,在人的肝癌、巨细胞型胶质母细胞瘤、乳腺癌、胶质肉瘤、食管癌和胃印戒细胞癌的肿瘤组织中都发现了不同程度的T3A抗体标记阳性细胞,而在正常肝、脑、食道和胃组织切片上未见到T3A抗体标记阳性的细胞。
结论：我们的研究结果表明,人的肿瘤干细胞具有分化成为不同肿瘤细胞的潜能,人的肿瘤细胞可能来源于一类共同的肿瘤干细胞。
Although the existence of cancer stem cells (CSCs) has been confirmed in some primary tumors and cancer cell lines, it has not been well documented whether cancer stem cells have the potential of differentiating into different types of cancer cells. Therefore, to investigate the multi-potential of cancer stem cells will have great significance for developing a novel anti-tumor method by targeting cancer stem cells as well as for elucidating the initiation, progression and metastasis of cancer.
Objectives: To investigate and confirm the potential that cancer stem cells could differentiate into different types of cancer cells.
Methods: A population of small cells (T3A) with rapidly proliferation capacity were obtained during isolation and culture of primary human liver cancer microvascular endothelial cells. Undergo subcutanously inoculation with NOD/SCID mice and monoclonal screening, a single cell clone (T3A-A3) with rapid proliferation and high tumorigenicity was selected by MTT assay and immune deficienct mice tumorigenesis. Expression of stem cell related genes was analyzed by RT-PCR in T3A-A3. The stem cell-related markers were detected by flow cytometry in T3A-A3. Self-renewal potential of T3A-A3 was evaluated by methylcellulose secondary colony fomation assay and secondary tumorigenesis assay. Chromosome karyotype assay was made with T3A-A3 tumorigenicity and metastasis ability was evaluated by subcutaneous inoculation and intrahepatic inoculation respectively.
In order to investigate the multiple differentiation potential of T3A-A3, human melanoma cell line SK-MEL-1 and human lymphoma cell line Daudi were selected to prepare the cancer inducing conditioned mediums (including cell conditioned mediums and tissue conditioned mediums):the cell conditioned mediums were made from culture supernatant of melanoma/lymphoma after incubated under hypoxia/reoxygenation, while the tissue conditioned medium were made from tissue homogenate of tumors formed by both cell transplanted in NOD/SCID mice. T3A-A3 was cultured with melanoma/lymphoma cell conditioned mediums or with melanoma/lymphoma tissue conditioned mediums for 21 days respectively, then the expression of melanoma specific molecule (gp100) and lymphoma correlative molecule (CD10) were detected by RT-PCR, immunofluorescence staining, western blot and immunohistochemistry technology.
In addition, the monoclonal antibody against T3A was developed and applied to immunohistochemistry staining on 6 types of human cancer tissues and 4 types of human normal tissues.
Results: By RT-PCR, mRNA of such genes related to stem cell proliferation and self-renewal as Notch, Bmi-1,β-catenin, Oct-4 and SMO were fund to express in T3A-A3. mRNA of several transcription factors related to induced pluripotent stem cell, Oct-4, Nanog, Lin28, K1f4, Sox2 and C-myc were expressed in T3A-A3 as well as stem cell classic markers CD133, CD34, ABCG2, Nestin, C-kit and SCF. By flow cytometry, expressions of the classic stem cell markers CD133,Nestin,CD34,CD44, ABCG2 and Oct-4 were confirmed on T3A-A3 cells. Chromosome karyotype analysis showed that T3A-A3 is polyploidy. The ability of secondary colony formation and secondary tumorigenicity ability were exhibited with T3A-A3 cells. Tumorigenesis was found when just 1000 T3A-A3 cells were subcutaneously inoculated into NOD/SCID mice. The metastatic focuses were found in stomach, lung and colon two months later 1×106 T3A-A3 cells were inoculated in NOD/SCID mice. The morphological changes were found in T3A-A3 cells after induced with melanoma/lymphoma cell conditioned mediums or melanoma/lymphoma tissue conditioned mediums. The specific marker of melanoma (gp100) was found in T3A-A3 after cultured with melanoma conditioned mediums or melanoma tissue mediums by RT-PCR, immunofluorescence staining, western blot and immunohistochemical staining. It was indicated that T3A-A3 was induced to differentiate toward melanoma cell. The fact specific marker of lymphoma (CD 10) was detectable in T3A-A3 after cultured with lymphoma cell conditioned mediums or tissue conditioned mediums by RT-PCR, immunofluorescence staining, western blot and immunohistochemical staining indicated that T3A-A3 was induced to differentiate toward to lymphoma cell. In addition, by immunohistochemical staining with mAb against T3A, positive cell subsets were detected in several different types of cancers including hepatoma, giant cell glioblastoma, breast cancer, gliosarcoma, esophageal cancer and gastric signet ring cell carcinoma.At the same time, no positive cell was detected in normal liver, normal brain, normal esophagus, and normal stomach tissues.
Conclusions:Human cancer stem cells have the potential of differentiating into different types of cancer cells, and the different types of cancer cells may come from one homogeneous cancer stem cells.
目的：研究和证实肿瘤干细胞具有分化成为不同肿瘤细胞的潜能。
方法：从原代人肝癌微血管内皮细胞分离培养过程中获得了一种快速增殖的小细胞(命名为T3A),通过将这些细胞在免疫缺陷小鼠成瘤和单细胞克隆技术筛选出生长最迅速、成瘤能力最强的细胞克隆(命名为T3A-A3)。对T3A-A3性质的鉴定分别应用]RT-PCR分析T3A-A3细胞干细胞相关基因mRNA的水平；应用流式细胞术从蛋白水平检测干细胞相关标志的表达；应用甲基纤维素二次集落形成实验及免疫缺陷小鼠二次成瘤实验评价T3A-A3细胞的自我更新能力；并通过染色体核型分析对T3A-A3细胞进行核型鉴定。通过将细胞接种于NOD/SCID鼠后的成瘤和转移情况评价T3A-A3细胞的成瘤能力。为诱导T3A-A3细胞向不同肿瘤细胞分化,选择人黑色素瘤细胞株(SK-MEL-1)和淋巴瘤细胞株(Daudi),用反复低氧-复氧培养分别活化两种肿瘤细胞,然后收集细胞的培养上清用作诱导分化的肿瘤细胞条件培养基,另将两种肿瘤细胞分别接种免疫缺陷小鼠,将成瘤后的肿瘤组织匀浆处理,用以制备肿瘤组织条件培养基。用黑色素瘤细胞和淋巴瘤细胞制备的细胞及组织条件培养基培养T3A-A3细胞21天后,应用RT-PCR、免疫蛋白印迹(Western-blot).细胞免疫荧光染色和免疫组织化学染色方法检测T3A-A3细胞诱导分化前后黑色素瘤细胞特有蛋白gp100和淋巴瘤细胞特异蛋白CD10的表达情况。
此外，通过免疫组织化学染色检测在人肝癌、巨细胞型胶质母细胞瘤、乳腺癌、胶质肉瘤、食管癌和胃印戒细胞癌,以及正常肝、脑、食道和胃组织切片上T3A单抗阳性细胞的分布情况。
结果：RT-PCR结果显示,T3A-A3细胞表达与干细胞增殖、自我更新相关的基因Notch-1, Bmi-1,β-catenin, Oct-4, SMO;表达经典的干细胞标志性分子CD133, CD34, ABCG2, Nestin, C-kit和SCF；表达可诱导的多潜能干细胞(induced pluripotent stem cells,iPS)相关的转录因子Oct-4, Nanog, Lin28, Klf4, Sox2和C-myc。流式细胞术分析显示,T3A-A3细胞表达经典干细胞标志性分子CD133、Nestin, CD34, CD44, ABCG2和Oct-4；二次集落形成实验及二次成瘤实验阳性。染色体核型分析显示,T3A-A3细胞为多倍体；细胞接种到NOD/SCID鼠皮下后,最低1000个细胞即可成瘤；接种1×106T3A-A3细胞于NOD/SCID鼠肝脏,2个月后在胃、肺、结肠发现肿瘤转移灶。T3A-A3细胞经过黑色素瘤细胞和黑色素瘤组织条件培养基诱导3周后,细胞形态发生明显变化,RT-PCR、Western-blot、细胞免疫荧光染色和免疫组织化学染色显示,T3A-A3细胞表达黑色素瘤细胞的特异标志gp100的mRNA和蛋白,表明T3A-A3向黑色素瘤细胞分化；T3A-A3细胞经过淋巴瘤细胞和淋巴瘤组织条件培养基诱导3周后,细胞形态也发生明显变化,RT-PCR、Western-blot、细胞免疫荧光染色和免疫组织化学染色显示,T3A-A3细胞表达淋巴瘤细胞的特异标志CD10的mRNA和蛋白,表明T3A-A3具有向淋巴瘤细胞分化的潜能。通过免疫组织化学染色,在人的肝癌、巨细胞型胶质母细胞瘤、乳腺癌、胶质肉瘤、食管癌和胃印戒细胞癌的肿瘤组织中都发现了不同程度的T3A抗体标记阳性细胞,而在正常肝、脑、食道和胃组织切片上未见到T3A抗体标记阳性的细胞。
结论：我们的研究结果表明,人的肿瘤干细胞具有分化成为不同肿瘤细胞的潜能,人的肿瘤细胞可能来源于一类共同的肿瘤干细胞。
Although the existence of cancer stem cells (CSCs) has been confirmed in some primary tumors and cancer cell lines, it has not been well documented whether cancer stem cells have the potential of differentiating into different types of cancer cells. Therefore, to investigate the multi-potential of cancer stem cells will have great significance for developing a novel anti-tumor method by targeting cancer stem cells as well as for elucidating the initiation, progression and metastasis of cancer.
Objectives: To investigate and confirm the potential that cancer stem cells could differentiate into different types of cancer cells.
Methods: A population of small cells (T3A) with rapidly proliferation capacity were obtained during isolation and culture of primary human liver cancer microvascular endothelial cells. Undergo subcutanously inoculation with NOD/SCID mice and monoclonal screening, a single cell clone (T3A-A3) with rapid proliferation and high tumorigenicity was selected by MTT assay and immune deficienct mice tumorigenesis. Expression of stem cell related genes was analyzed by RT-PCR in T3A-A3. The stem cell-related markers were detected by flow cytometry in T3A-A3. Self-renewal potential of T3A-A3 was evaluated by methylcellulose secondary colony fomation assay and secondary tumorigenesis assay. Chromosome karyotype assay was made with T3A-A3 tumorigenicity and metastasis ability was evaluated by subcutaneous inoculation and intrahepatic inoculation respectively.
In order to investigate the multiple differentiation potential of T3A-A3, human melanoma cell line SK-MEL-1 and human lymphoma cell line Daudi were selected to prepare the cancer inducing conditioned mediums (including cell conditioned mediums and tissue conditioned mediums):the cell conditioned mediums were made from culture supernatant of melanoma/lymphoma after incubated under hypoxia/reoxygenation, while the tissue conditioned medium were made from tissue homogenate of tumors formed by both cell transplanted in NOD/SCID mice. T3A-A3 was cultured with melanoma/lymphoma cell conditioned mediums or with melanoma/lymphoma tissue conditioned mediums for 21 days respectively, then the expression of melanoma specific molecule (gp100) and lymphoma correlative molecule (CD10) were detected by RT-PCR, immunofluorescence staining, western blot and immunohistochemistry technology.
In addition, the monoclonal antibody against T3A was developed and applied to immunohistochemistry staining on 6 types of human cancer tissues and 4 types of human normal tissues.
Results: By RT-PCR, mRNA of such genes related to stem cell proliferation and self-renewal as Notch, Bmi-1,β-catenin, Oct-4 and SMO were fund to express in T3A-A3. mRNA of several transcription factors related to induced pluripotent stem cell, Oct-4, Nanog, Lin28, K1f4, Sox2 and C-myc were expressed in T3A-A3 as well as stem cell classic markers CD133, CD34, ABCG2, Nestin, C-kit and SCF. By flow cytometry, expressions of the classic stem cell markers CD133,Nestin,CD34,CD44, ABCG2 and Oct-4 were confirmed on T3A-A3 cells. Chromosome karyotype analysis showed that T3A-A3 is polyploidy. The ability of secondary colony formation and secondary tumorigenicity ability were exhibited with T3A-A3 cells. Tumorigenesis was found when just 1000 T3A-A3 cells were subcutaneously inoculated into NOD/SCID mice. The metastatic focuses were found in stomach, lung and colon two months later 1×106 T3A-A3 cells were inoculated in NOD/SCID mice. The morphological changes were found in T3A-A3 cells after induced with melanoma/lymphoma cell conditioned mediums or melanoma/lymphoma tissue conditioned mediums. The specific marker of melanoma (gp100) was found in T3A-A3 after cultured with melanoma conditioned mediums or melanoma tissue mediums by RT-PCR, immunofluorescence staining, western blot and immunohistochemical staining. It was indicated that T3A-A3 was induced to differentiate toward melanoma cell. The fact specific marker of lymphoma (CD 10) was detectable in T3A-A3 after cultured with lymphoma cell conditioned mediums or tissue conditioned mediums by RT-PCR, immunofluorescence staining, western blot and immunohistochemical staining indicated that T3A-A3 was induced to differentiate toward to lymphoma cell. In addition, by immunohistochemical staining with mAb against T3A, positive cell subsets were detected in several different types of cancers including hepatoma, giant cell glioblastoma, breast cancer, gliosarcoma, esophageal cancer and gastric signet ring cell carcinoma.At the same time, no positive cell was detected in normal liver, normal brain, normal esophagus, and normal stomach tissues.
Conclusions:Human cancer stem cells have the potential of differentiating into different types of cancer cells, and the different types of cancer cells may come from one homogeneous cancer stem cells.
引文
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