淫羊藿素联合达拉菲尼抑制黑素瘤增殖和转移

目的探讨淫羊藿素联合达拉菲尼对人黑素瘤A375细胞增殖和转移的抑制作用及可能的机制。方法采用不同浓度淫羊藿素和达拉菲尼单独及联合作用于A375细胞;CCK-8法检测细胞生长抑制率,进行协同性分析;Transwell和划痕实验检测细胞迁移和侵袭能力;qPCR及Westernblot检测MMP-2、MMP-9、Vimentin和E-cadherin的表达情况。结果淫羊藿素和达拉菲尼均能下调A375细胞MMP-2、MMP-9和Vimentin的表达,上调E-cadherin的表达,抑制其增殖、迁移和侵袭,且两药低浓度联合具有协同效应。结论淫羊藿素能协同达拉菲尼抑制A375细胞MMP-2、MMP-9和Vimentin的表达,促进E-cadherin的表达,抑制黑素瘤细胞的增殖和转移。     

麦冬皂苷B通过抑制PI3K/Akt/mTOR通路诱导人黑色素瘤A375细胞凋亡

目的探讨麦冬皂苷B对人黑色素瘤(Melanoma)A375细胞增殖,凋亡和细胞周期的影响以及相关机制。方法麦冬皂苷B处理A375细胞后,采用CCK-8法检测细胞活力;流式细胞仪检测A375细胞周期变化及细胞凋亡水平;Hoechst33258荧光染色法观察细胞凋亡形态;免疫印迹法检测麦冬皂苷B对A375细胞PI3K,p-PI3K,AKT,p-AKT蛋白以及通路下游凋亡相关蛋白Bcl-2,Bax,Cleaved-caspase3表达的影响。结果麦冬皂苷B能抑制A375细胞增殖活力及PI3K/Akt/mTOR通路的活化;麦冬皂苷B促进了A375细胞内Bax和Cleaved-caspase 3的表达,抑制Bcl-2表达,诱导人黑色素瘤细胞发生凋亡;麦冬皂苷B阻滞了A375细胞细胞周期,G0/G1期细胞比例明显升高;PI3K/Akt/mTOR通路活化剂IGF-1处理A375细胞后抑制了麦冬皂苷B的上述作用。结论麦冬皂苷B能抑制A375细胞的增殖,诱导细胞发生凋亡,阻滞细胞周期于G0/G1期。     

uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.     

口腔黏膜恶性黑色素瘤颈部淋巴结转移规律及颈部预防治疗的价值

目的 分析口腔黏膜恶性黑色素瘤(OMM)颈部淋巴结转移规律以及颈部预防治疗的价值。方法 回顾性分析中国医学科学院肿瘤医院1984-2016年间收治的61例无远处转移的OMM病例的颈部淋巴结转移规律,颈部预防治疗疗效,失败模式及预后因素。结果 OMM颈部淋巴结转移率为55.7%。Ⅰ b区是最常见的颈部淋巴结转移区域,占颈部淋巴结转移患者的76%,其次是Ⅱ区和Ⅲ区。对于cN0患者,接受至少同侧Ⅰ b-Ⅲ区颈部预防治疗和未接受的5年无区域复发生存率分别为91.7%和52.4%(P=0.036),接受至少同侧Ⅰ b-Ⅲ区颈部预防治疗能将区域失败率由46%降至6%(P=0.035)。发生区域失败患者中93%发生在Ⅰ b区,50%发生在Ⅱ区,36%发生在Ⅲ区。结论 OMM颈部淋巴结转移率较高,淋巴结引流具有一定规律性,最常见转移和复发部位均为Ⅰ b-Ⅲ区。对于cN0的OMM,推荐至少包括同侧颈部Ⅰ b-Ⅲ区的预防治疗。     

The role of exosomes in metastasis and progression of melanoma

The mechanisms of melanoma metastasis have been the subject of extensive research for decades. Improved diagnostic and therapeutic strategies are of increasing importance for the treatment of melanoma due to its high burden of mortality in the advanced stages of the disease. Intercellular communication is a critical event for the progression of cancer. Collective evidence suggests that exosomes, small extracellular membrane vesicles released by the cells, are important facilitators of intercellular communication between the cells and the surrounding environment. Although the emerging field of exosomes is rapidly gaining traction in the scientific community, there is limited knowledge regarding the role of exosomes in melanoma. This review discusses the multifaceted role of melanoma-derived exosomes in promoting the process of metastasis by modulating the invasive and angiogenic capacity of malignant cells. The future implications of exosome research and the therapeutic potential of exosomes are also discussed.     

免疫检查点抑制剂联合治疗：从机制到临床

近年来免疫检查点抑制剂（immune checkpoint inhibitor,ICI）陆续获批用于多种恶性肿瘤的治疗,为患者带来新的希望。但在一些瘤种中ICI单药客观缓解率仅10%~20%,如何提高临床获益是免疫相关临床研究关注的重点。近期研究显示,联合不同机制的ICI有助于提高缓解率和发挥持久的抗肿瘤作用,合适的剂量方案也能合理平衡疗效和安全性。拟对ICI联合治疗的机制、药代动力学和临床研究进展进行综述。