PO.TB07.03 · 肿瘤生物学
癌细胞来源的TWEAK在促进卵巢癌细胞癌症干细胞样表型中的作用
The role of cancer cell-derived TWEAK in promoting a cancer stem-like phenotype in ovarian cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌是美国最致命的妇科癌症，超过80%的患者在化疗后复发。复发性卵巢癌可能是由具有耐药性、能够长期自我更新并重建肿瘤的癌症干细胞样细胞（CSCs）所致。本实验室既往研究提示，TWEAK——一种在卵巢肿瘤中富集的细胞因子——增强CSC的发育和存活。此外，在小鼠模型中，将抑制TWEAK与化疗联合应用可显著延长生存和缓解期。卵巢癌中TWEAK的来源尚未明确，但在正常组织中它主要由髓系细胞产生。近期一项胰腺癌研究鉴定癌细胞为TWEAK的一种新来源，而本实验室的初步数据提示，卵巢癌细胞中TWEAK蛋白表达在化疗处理后显著增加（2倍）。因此，我们假设癌细胞来源的TWEAK是卵巢癌细胞CSC表型的独特驱动因素。为验证该假设，我们在OVCAR8和CAOV4卵巢癌细胞系中构建并验证了TWEAK的shRNA敲低（基因和蛋白水平）。为评估TWEAK介导的肿瘤形成，我们在shNeg和shTWEAK细胞中分选CSCs和非CSCs，并将细胞腹腔注射入异种移植小鼠模型。我们发现，与非CSC shNeg肿瘤相比，非CSC shTWEAK肿瘤的肿瘤形成显著减少（p<0.05）。此外，与shNeg非CSCs和shTWEAK CSCs相比，shTWEAK非CSCs中计算的干细胞频率显著降低（分别为p=0.0144和p=0.0086）。这些数据提示干细胞频率依赖于TWEAK表达。目前正在开展实验，以评估CSC和非CSC shNeg与shTWEAK细胞的球体形成能力、化疗耐药性及干性基因的表达。通过靶向TWEAK等促进CSC表型的因子，我们希望能够鉴定出替代性治疗策略，以抑制CSC的发育并预防卵巢癌复发。
查看英文原文 English abstract
Ovarian cancer is the most lethal gynecological cancer in the United States, with over 80% of patients relapsing after chemotherapy. Recurrent ovarian cancer may be due to cancer stem-like cells (CSCs) that are drug resistant and capable of long-term self-renewal and reestablishment of tumors. Previous studies in our lab suggest that TWEAK, a cytokine enriched in ovarian tumors, enhances CSC development and survival. Additionally, inhibiting TWEAK in combination with chemotherapy was shown to significantly prolong survival and remission in mouse models. The source of TWEAK in ovarian cancer remains unidentified, but in normal tissues it is primarily produced by myeloid cells. A recent pancreatic cancer study identified cancer cells as a novel source of TWEAK and preliminary data from our lab suggests that TWEAK protein expression in ovarian cancer cells is significantly increased (2-fold) following chemotherapy treatment. Therefore, we hypothesize that cancer cell-derived TWEAK is a unique driver of CSC phenotypes in ovarian cancer cells. To explore this hypothesis, we generated and validated shRNA knockdown of TWEAK in OVCAR8 and CAOV4 ovarian cancer cell lines at the gene and protein level. To assess TWEAK-mediated tumor formation, we sorted for CSCs and non-CSCs in shNeg and shTWEAK cells and intraperitoneally injected cells into a xenograft mouse model. We found significantly decreased tumor formation in non-CSC shTWEAK tumors compared to non-CSC shNeg tumors (p<0.05). Moreover, the calculated stem cell frequency was significantly reduced in the shTWEAK non-CSCs compared to the shNeg non-CSCs and shTWEAK CSCs (p=0.0144 and p=0.0086, respectively). This data suggests that stem cell frequency is dependent on TWEAK expression. Experiments are underway to assess spheroid formation ability, chemoresistance, and expression of stemness genes in the CSC and non-CSC shNeg and shTWEAK cells. By targeting factors like TWEAK that promote a CSC phenotype, we hope to identify alternative therapeutic strategies to inhibit CSC development and prevent relapse in ovarian cancer.
利益披露 Disclosure
S. Mathew, None..
L. S. Cruz, None.