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Breast Cancer Disseminated Tumor Cells: Do They Stay and Fight or Run and Hide? 乳腺癌扩散的肿瘤细胞:它们是留下来战斗还是逃跑躲藏?
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-15 DOI: 10.1158/0008-5472.can-24-2408
Frank C Cackowski,Hasan Korkaya
Many solid tumors including breast cancer can exhibit early dissemination and dormancy-in which cancer cells spread early in the disease process and survive long periods without detectable growth. These early disseminated tumor cells sometimes reactivate and lead to incurable metastatic disease years or even decades after curative-intent therapy for the primary tumor. We are just beginning to understand the role of the immune system in this process in part because of improvements in immunocompetent models as well as technological advances such as single-cell genomics and spatial transcriptomics. In this issue of Cancer Research, Bushnell and colleagues showed that NK cells are important in this context. The authors found that disseminated tumor cells and quiescent cells express higher levels of MHC 1 but are resistant to NK-cell-mediated immunity. The proposed mechanism involves the STING pathway and transcription factors Sox2 and Bach1. As other studies have highlighted the importance of T-cell immunity, this work reaffirms the importance and diversity of immune regulation of dormancy and suggests the need for future studies to flesh out mechanistic details and predict when each type of immunity is most important. See related article by Bushnell et al., p. 3337.
包括乳腺癌在内的许多实体瘤都会出现早期扩散和休眠--即癌细胞在疾病过程的早期扩散,并在没有检测到生长的情况下存活很长时间。这些早期扩散的肿瘤细胞有时会重新活化,并在原发肿瘤接受治愈性治疗数年甚至数十年后导致无法治愈的转移性疾病。我们刚刚开始了解免疫系统在这一过程中的作用,部分原因是免疫能力模型的改进以及单细胞基因组学和空间转录组学等技术的进步。在本期《癌症研究》(Cancer Research)杂志上,Bushnell及其同事发现NK细胞在这一过程中非常重要。作者发现,扩散的肿瘤细胞和静止细胞表达较高水平的 MHC 1,但对 NK 细胞介导的免疫具有抵抗力。所提出的机制涉及 STING 通路以及转录因子 Sox2 和 Bach1。由于其他研究强调了 T 细胞免疫的重要性,这项工作再次证实了休眠免疫调节的重要性和多样性,并表明今后的研究需要充实机制细节,并预测每种类型的免疫何时最重要。参见 Bushnell 等人的相关文章,第 3337 页。
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引用次数: 0
Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation. 靶向 YAP 活性和谷氨酰胺代谢可通过防止细胞外基质积累而协同抑制肿瘤进展
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-15 DOI: 10.1158/0008-5472.CAN-23-3933
Mihyang Park, Jonghwa Jin, Da Young An, Dong-Ho Kim, Jaebon Lee, Jae Won Yun, Ilseon Hwang, Jae Seok Park, Mi Kyung Kim, You Mie Lee, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park

Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate/protein kinase A (PKA)-dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing the secretion of connective tissue growth factor that promoted the production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors. Significance: Blocking glutamine utilization activates YAP to promote ECM deposition by fibroblasts, highlighting the potential of YAP inhibitors and antifibrotic strategies as promising approaches for effective combination metabolic therapies in cancer.

癌细胞利用多种机制来逃避谷氨酰胺代谢抑制剂的作用。肿瘤内谷氨酰胺可用性改变的反应途径可能是这些抑制剂组合策略的治疗目标。在这里,我们研究发现,谷氨酰胺的利用会降低环磷酸腺苷(cAMP)/蛋白激酶A(PKA)依赖的大肿瘤抑制因子(LATS)磷酸化,从而刺激癌细胞中的Yes相关蛋白(YAP)信号转导。YAP 活化的升高会增加结缔组织生长因子(CTGF)的分泌,促进周围成纤维细胞产生纤维粘连蛋白和胶原蛋白,从而诱导细胞外基质(ECM)沉积。因此,抑制 YAP 与抑制谷氨酰胺利用协同作用,可有效抑制体内肿瘤生长,同时减少 ECM 沉积。阻断 ECM 重塑也增强了谷氨酰胺利用抑制剂的抑瘤效果。总之,这些数据揭示了针对谷氨酰胺利用增加 ECM 积累的机制,并确定了降低 ECM 水平和提高谷氨酰胺代谢抑制剂疗效的潜在策略。
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引用次数: 0
SpatialDeX is a Reference-Free Method for Cell Type Deconvolution of Spatial Transcriptomics Data in Solid Tumors SpatialDeX 是一种用于实体瘤空间转录组学数据细胞类型解卷积的无参照方法
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 DOI: 10.1158/0008-5472.can-24-1472
Xinyi Liu, Gongyu Tang, Yuhao Chen, Yuanxiang Li, Hua Li, Xiaowei Wang
The rapid development of spatial transcriptomics (ST) technologies has enabled transcriptome-wide profiling of gene expression in tissue sections. Despite the emergence of single-cell resolution platforms, most ST sequencing studies still operate at a multi-cell resolution. Consequently, deconvolution of cell identities within the spatial spots has become imperative for characterizing cell type-specific spatial organization. To this end, we developed SpatialDeX, a regression model-based method for estimating cell type proportions in tumor ST spots. SpatialDeX exhibited comparable performance to reference-based methods and outperformed other reference-free methods with simulated ST data. Using experimental ST data, SpatialDeX demonstrated superior performance compared with both reference-based and reference-free approaches. Additionally, a pan-cancer clustering analysis on tumor spots identified by SpatialDeX unveiled distinct tumor progression mechanisms both within and across diverse cancer types. Overall, SpatialDeX is a valuable tool for unraveling the spatial cellular organization of tissues from ST data without requiring scRNA-seq references.
空间转录组学(ST)技术的飞速发展使得对组织切片中的基因表达进行全转录组分析成为可能。尽管出现了单细胞分辨率平台,但大多数 ST 测序研究仍以多细胞分辨率进行。因此,要描述细胞类型特异性空间组织的特征,就必须对空间点内的细胞特征进行解卷积。为此,我们开发了一种基于回归模型的方法--SpatialDeX,用于估计肿瘤ST斑点中的细胞类型比例。SpatialDeX 的性能与基于参考的方法不相上下,在模拟 ST 数据中的表现优于其他无参考方法。在使用实验 ST 数据时,SpatialDeX 的性能优于基于参考和无参考的方法。此外,对 SpatialDeX 确定的肿瘤点进行的泛癌症聚类分析揭示了不同癌症类型内部和之间不同的肿瘤进展机制。总之,SpatialDeX 是一种有价值的工具,无需 scRNA-seq 参考即可从 ST 数据中揭示组织的空间细胞组织。
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引用次数: 0
Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer. 用临床激动剂Riociguat刺激可溶性鸟苷酸环化酶可抑制阉割耐药前列腺癌的发展和恶化
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 DOI: 10.1158/0008-5472.CAN-24-0133
Ling Zhang, Clara I Troccoli, Beatriz Mateo-Victoriano, Laura Misiara Lincheta, Erin Jackson, Ping Shu, Trisha Plastini, Wensi Tao, Deukwoo Kwon, X Steven Chen, Janaki Sharma, Merce Jorda, Surinder Kumar, David B Lombard, James L Gulley, Marijo Bilusic, Albert C Lockhart, Annie Beuve, Priyamvada Rai

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second-leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. Here, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared to their castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer (CSPC) populations, the obligate sGC heterodimer was repressed via methylation of its beta subunit. Genetically abrogating sGC complex formation in CSPC cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and co-treatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy.

阉割抵抗性前列腺癌(CRPC)是一种无法治愈的致命疾病,使前列腺癌成为美国男性第二大癌症死因。CRPC是对常规雄激素剥夺(AD)治疗产生耐药性的结果,其分子机制尚不完全清楚,缺乏持久的治疗方案。在这里,我们发现可溶性鸟苷酸环化酶(sGC)信号的增强是抑制CRPC启动和生长的一种机制。侵袭性、致命性CRPC患者血清中sGC催化产物环GMP(cGMP)的水平明显低于对阉割敏感的患者。在从对绝经敏感的前列腺癌(CSPC)群体中分离出的新出现的绝经抗性细胞中,必须的sGC异二聚体通过其β亚基的甲基化而受到抑制。在 CSPC 细胞中从基因上废除 sGC 复合物的形成,可促进逃避 AD 诱导的衰老,同时促进耐阉割肿瘤的生长。在已建立的抗阉割细胞中,sGC复合物虽然存在,但处于可逆氧化和非活性状态。将 CRPC 细胞置于 AD 中可再生出功能性复合物,与 FDA 批准的 sGC 激动剂 Riociguat 联合处理可诱发氧化还原压力诱导的细胞凋亡。Riociguat 降低了耐阉割肿瘤的生长,增加了凋亡标志物,cGMP 水平的升高与肿瘤负荷的降低有显著相关性。Riociguat 治疗重组了肿瘤血管,消除了缺氧肿瘤龛,减少了 CD44+ 肿瘤祖细胞,提高了阉割耐药肿瘤的放射敏感性。因此,本研究表明,增强sGC活性可通过肿瘤细胞内在和外在效应抑制CRPC的出现和进展。可将 Riociguat 重新用于治疗 CRPC,并将 cGMP 水平的无创监测作为靶向疗效的标志物。
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引用次数: 0
C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis C反应蛋白通过激活肺巨噬细胞中的FcγR2B诱导免疫抑制,促进肺转移
IF 11.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-10 DOI: 10.1158/0008-5472.can-24-0253
Jun-Rui Feng, Xue Li, Cong Han, Yue Chang, Yu Fu, Gong-Chang Feng, Yutiantian Lei, Hai-Yun Li, Patrick Ming-Kuen Tang, Shang-Rong Ji, Yuzhu Hou, Yi Wu
C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a pre-metastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics.
C反应蛋白(CRP)是一种来源于肝脏的急性时相反应物,是与癌症预后不良相关的炎症临床标志物。在许多类型的癌症中都可观察到 CRP 水平升高,并且与转移风险显著增加有关,这表明 CRP 可能具有促进转移的作用。在此,我们报告了 CRP 通过抑制乳腺癌和黑色素瘤肺巨噬细胞的抗癌能力来促进肺转移。与野生型小鼠相比,缺失 CRP 的小鼠可抑制乳腺癌和黑色素瘤细胞的肺转移,而对肿瘤生长无明显影响。此外,CRP缺失小鼠的肺部富含活化的肺巨噬细胞,通过全身注射人CRP可将其减少到野生型小鼠的水平。从机理上讲,CRP以FcγR2B依赖的方式阻断了共生细菌诱导的肺巨噬细胞活化,从而损害了巨噬细胞介导的免疫监视,促进了肿瘤小鼠肺部转移前生态位的形成。因此,用特异性CRP抑制剂治疗可激活肺巨噬细胞并减轻体内肺转移。这些发现强调了CRP在肺转移中的重要性,它可能是临床上晚期实体瘤患者的有效治疗靶点。
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引用次数: 0
LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer. LSD1 和 CoREST2 可增强 STAT3 的活性,促进黏液性结直肠癌的肠内分泌细胞分化。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/0008-5472.CAN-24-0788
Christopher A Ladaika, Ahmed H Ghobashi, William C Boulton, Samuel A Miller, Heather M O'Hagan

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron-like characteristics. Furthermore, LSD1 and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

神经内分泌细胞与许多癌症类型的耐药性和总体生存率下降有关。与非粘液性结肠直肠癌(mCRC)相比,粘液性结肠直肠癌(mCRC)特有的肠内分泌细胞(EECs)(正常结肠上皮的神经内分泌细胞)富集。因此,针对 EEC 的分化可能对 mCRC 有临床价值。在这里,单细胞多组学发现了伴随EEC分化的表观遗传学改变,确定了STAT3是EEC分化的调控因子,并发现了一种具有肠神经元样特征的罕见癌症特异性细胞类型。此外,LSD1和CoREST2介导了STAT3去甲基化并增强了STAT3染色质结合。在正位异种移植小鼠模型中敲除 CoREST2 可减少原发性肿瘤的生长和肺转移。总之,这些结果为开发针对 LSD1 与 STAT3 或 CoREST2 之间相互作用的 LSD1 抑制剂提供了理论依据,从而可能改善 mCRC 患者的临床疗效。
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引用次数: 0
Impact of Structural Racism and Social Determinants of Health on Disparities in Breast Cancer Mortality. 结构性种族主义和健康的社会决定因素对乳腺癌死亡率差异的影响。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-02 DOI: 10.1158/0008-5472.CAN-24-1359
Mary Falcone, Bodour Salhia, Chanita Hughes Halbert, Evanthia T Roussos Torres, Daphne Stewart, Mariana C Stern, Caryn Lerman

The striking ethnic and racial disparities in breast cancer mortality are not explained fully by pathological or clinical features. Structural racism contributes to adverse conditions that promote cancer inequities, but the pathways by which this occurs are not fully understood. Social determinants of health (SDOH), such as economic status and access to care, account for a portion of this variability, yet interventions designed to mitigate these barriers have not consistently led to improved outcomes. Based on the current evidence from multiple disciplines, we describe a conceptual model in which structural racism and racial discrimination contribute to increased mortality risk in diverse groups of patients by promoting adverse SDOH that elevate exposure to environmental hazards and stress; these exposures in turn contribute to epigenetic and immune dysregulation, thereby altering breast cancer outcomes. Based on this model, opportunities and challenges arise for interventions to reduce racial and ethnic disparities in breast cancer mortality.

病理或临床特征并不能完全解释乳腺癌死亡率中存在的显著的民族和种族差异。结构性种族主义造成了助长癌症不平等的不利条件,但这种情况发生的途径还不完全清楚。健康的社会决定因素(SDOH),如经济状况和获得医疗服务的机会,是造成这种差异的部分原因,但旨在缓解这些障碍的干预措施并没有持续改善结果。根据目前来自多个学科的证据,我们描述了一个概念模型,在该模型中,结构性种族主义和种族歧视通过促进不利的 SDOH,增加暴露于环境危害和压力的机会,从而导致不同患者群体的死亡风险增加;这些暴露反过来又会导致表观遗传和免疫失调,从而改变乳腺癌的预后。基于这一模式,为减少乳腺癌死亡率中的种族和民族差异而采取的干预措施既面临机遇,也面临挑战。
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引用次数: 0
Induction of the TEAD Co-activator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer. 雌激素受体靶向疗法诱导 TEAD 协同激活因子 VGLL1 引发乳腺癌抗药性
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-02 DOI: 10.1158/0008-5472.CAN-24-0013
Carolina Gemma, Chun-Fui Lai, Anup K Singh, Antonino Belfiore, Neil Portman, Heloisa Z Milioli, Manikandan Periyasamy, Sara Raafat, Alyssa J Nicholls, Claire M Davies, Naina R Patel, Georgia M Simmons, Hailing Fan, Van T M Nguyen, Luca Magnani, Emad Rakha, Lesley-Ann Martin, Elgene Lim, R Charles Coombes, Giancarlo Pruneri, Laki Buluwela, Simak Ali

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer, and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co-activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients.

雌激素受体(ER)阳性乳腺癌对内分泌疗法(ET)的耐药性很常见,大多数复发患者都死于 ET 耐药性疾病。虽然基因突变可以解释某些复发,但在许多情况下,耐药机制仍未确定。药物诱导的表观遗传学重编程已被证明提供了可能的抗药性途径。通过分析ET耐药模型中组蛋白H3赖氨酸27乙酰化(H3K27ac)谱和转录重编程,我们发现选择性ER降解剂(SERDs),如氟维司群,可促进TEAD转录因子的共激活剂VGLL1的表达。VGLL1 通过 TEAD 起作用,促进了驱动氟维司群抗性乳腺癌细胞生长的基因的表达。药物破坏 VGLL1/TEAD4 的相互作用抑制了 VGLL1/TEAD 诱导的转录程序,从而阻止了耐药细胞的生长。表皮生长因子受体(EGFR)是 VGLL1/TEAD 调控基因之一,VGLL1 引导的表皮生长因子受体(EGFR)上调可使对氟维司群有耐药性的乳腺癌细胞对表皮生长因子受体(EGFR)抑制剂敏感。综上所述,这些发现确定了 VGLL1 是 ET 抗性的转录驱动因子,为复发性 ER+ 乳腺癌患者的治疗提供了更多可能性。
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引用次数: 0
HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment. HIF1α 可抵消 TGFβ1 驱动的 TSP1 在内皮细胞中的表达,从而刺激缺氧肿瘤微环境中的血管生成。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-02 DOI: 10.1158/0008-5472.CAN-24-2324
Yu-Wei Luo, Yang Fang, Hui-Xian Zeng, Yu-Chen Ji, Meng-Zhi Wu, Hui Li, Jie-Ying Chen, Li-Min Zheng, Jian-Hong Fang, Shi-Mei Zhuang

Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.

新的证据表明,转化生长因子β1(TGFβ1)可抑制血管生成,这与肿瘤微环境中血管生成活跃和TGFβ1大量存在的现象相矛盾。在此,我们研究了肿瘤如何克服TGFβ1的抗血管生成作用。TGFβ1治疗抑制了小鸡绒毛膜和斑马鱼模型的生理性血管生成,但不影响小鼠肝癌异种移植的血管生成。低氧诱导因子 1α(HIF1α)抑制剂可恢复 TGFβ1 对小鼠异种移植血管生成的抑制作用。与此相反,HIF1α稳定剂可抑制斑马鱼的血管生成,这表明缺氧可能会削弱 TGFβ1 的抗血管生成作用。在正常缺氧条件下,TGFβ1通过TGFβ I型受体(TGFβR1)-SMAD2/3信号传导上调内皮细胞(ECs)中的抗血管生成因子thrombospondin 1(TSP1),从而抑制血管生成。在缺氧微环境中,HIF1α会诱导microRNA-145(miR145)的表达;miR145通过结合和抑制SMAD2/3的表达,进而降低EC中TSP1的水平,从而消除TGFβ1对血管生成的抑制作用。与邻近非肿瘤肝脏的心血管细胞相比,从人类肝细胞癌(HCC)中分离出的原发性心血管细胞显示出 miR145 增加、SMAD3 和 TSP1 减少。ECs中SMAD3或TSP1的减少与HCC组织中血管生成的增加有关。总之,本研究发现,ECs中的TGFβ1-TGFβR1-SMAD2/3-TSP1信号传导抑制了血管生成。缺氧-HIF1α-miR145轴可以规避这种抑制作用,从而阐明了缺氧促进血管生成的机制。
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引用次数: 0
Resistance Management for Cancer: Lessons from Farmers. 癌症的抗药性管理:农民的经验教训。
IF 12.5 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-02 DOI: 10.1158/0008-5472.CAN-23-3374
Sareh Seyedi, Valerie K Harris, Stefania E Kapsetaki, Shrinath Narayanan, Daniel Saha, Zachary Compton, Rezvan Yousefi, Alexander May, Efe Fakir, Amy M Boddy, Marco Gerlinger, Christina Wu, Lida Mina, Silvie Huijben, Dawn H Gouge, Luis Cisneros, Peter C Ellsworth, Carlo C Maley

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed ten principles that could be translated to controlling cancers: (1) prevent onset, (2) monitor continuously, (3) identify thresholds below which there will be no intervention, (4) change interventions in response to burden, (5) preferentially select non-chemical control methods, (6) use target-specific drugs, (7) use the lowest effective dose, (8) reduce cross-resistance, (9) evaluate success based on long-term management, and (10) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

我们无法治愈癌症的主要原因之一是,治疗方法会选择出抗药性细胞。害虫管理者也面临着类似的挑战,杀虫剂会选择出抗药性昆虫,从而产生类似的抗药性机制。害虫管理者已经制定了十项原则,这些原则可以转化为控制癌症的原则:(1)预防发病;(2)持续监测;(3)确定阈值,低于阈值将不予干预;(4)根据负担改变干预措施;(5)优先选择非化学控制方法;(6)使用靶向药物;(7)使用最低有效剂量;(8)减少交叉抗药性;(9)根据长期管理评估成功与否;(10)预测生长和反应。这些原则适用于所有癌症和抗癌药物,因此可广泛用于改善肿瘤学。在此,我们回顾了在控制害虫和癌细胞抗药性方面遇到的并行困难。我们展示了如何将害虫抗药性管理原则应用于癌症。害虫综合防治启发了肿瘤适应性疗法的发展,以提高癌症患者的无进展生存期和生活质量,而这是不可能治愈的。这些害虫管理原则有可能为临床试验设计提供参考。
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引用次数: 0
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Cancer research
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