Dormancy in a model of murine B cell lymphoma

A B cell lymphoma model of dormancy in mice was established by prior immunization to the B cell membrane immunoglobulin idiotype. The antibody to the idiotype was the major factor in inducing and maintaining dormancy and acted primarily as an agonist rather than via effector functions. CD8+ T cells synergized with anti-Id in inducing dormancy by secreting IFN-gamma. Cycling in the dormant population was reduced 3-5 fold, but each mouse contained approximately 10(6) tumor cells in its spleen, some of which were cycling, during the 1.5 years of observation. Thus, replication is balanced by cell death.     

肿瘤休眠研究现状

肿瘤休眠(tumor dormancy)临床上常见于原发肿瘤行根治性切除后,患者体内存在微小瘤灶或微量肿瘤细胞,在一定时间范围内既没有被机体清除,也没有增殖生长,但这些肿瘤细胞仍具有增殖潜能,可在数年乃至数十年后再次增殖,导致肿瘤的复发或远处转移.     

肿瘤休眠与血管新生

肿瘤休眠是指肿瘤细胞在宿主体内持续存在而没有明显生长的一种状态,存在复发和转移的可能性,是恶性肿瘤难以彻底根治的根源之一。现在研究表明血管新生与肿瘤演进密切相关。本文从血管新生与肿瘤休眠的关系,肿瘤休眠模型的建立,肿瘤休眠的研究方法,休眠标志物的检测等方面进行了论述。旨在为阐明血管生成与肿瘤休眠的关系,以及临床应用抗血管生成疗法治疗肿瘤提供有益的线索。     

TBK1 Regulates Prostate Cancer Dormancy through mTOR Inhibition

The mechanisms that regulate hematopoietic stem cell (HSC) dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa) cells target the HSC niche in mouse bone marrow (BM) during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1) on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR) and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.     

Angiogenesis Sustains Tumor Dormancy in Patients with Breast Cancer Treated with Adjuvant Chemotherapy

Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed.     

Dormancy versus extinction of mouse Leydig cell tumors following endocrine-induced regression

Although a majority of malignant testicular Leydig cell tumors induced in the mouse by chronic estrogenization remain dependent upon estrogen stimulation for growth during early transplant generations, we have observed tumors of two lines, no longer growth dependent upon estrogen, that regressed when hosts bearing palpable tumor grafts were given the same dosage of diethylstilbestrol that had induced the original tumors. Both estrogen-"dependent" and -"responsive" tumors were found to possess a similar estrogen receptor system. The present study compares light and electron microscopic changes occurring during regression and determines the ultimate outcome of the process under these seemingly opposite endocrine conditions. The individual neoplastic cells of the dependent tumors decreased in size, mitochondria with typical tubular cristae rapidly converted to a fully condensed configuration, and endoplasmic reticulum, both rough and smooth, as well as polyribosomes gradually disappeared. A few dormant, RNA-depleted tumor cells always remained, however. After 5 months of dormancy, mitotic activity was induced in many of these cells in 2 to 3 days by reinstituting estrogen administration. This activity began prior to conversion of the mitochondria to an orthodox configuration, to the accumulation of cytochemically demonstrable RNA, or to the appearance of RNA-containing organelles. These observations suggest that at least many of the dormant tumor "stem" cells had been blocked in G2. Contrariwise, the cytoplasmic volumes of the cells of regressing estrogen-responsive tumors increased with a considerable accumulation of lipid droplets, while alterations of the cytoplasmic organelles were much less marked, the mitochondria retaining their pretherapy morphology. Biochemical studies confirmed the fact that, although DNA synthesis ceased within a few days. RNA synthesis was maintained at a near normal level, at least during the first month of tumor regression, during which time the RNA to DNA ratio increased significantly. After 2 months or more of a sustained complete remission, no tumor cells could be found at the transplantation sites, and removing the estrogenic stimulus did not result in tumor regrowth. In short, the treatment had completely obliterated the cancer. It is concluded, therefore, that the molecular events that result in tumor regression from these diametrically opposite endocrine therapies must differ significantly. Both bring about an abrupt cessation of mitotic activity in the neoplastic cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

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An Experimental Model of Tumor Dormancy Therapy for Advanced Head and Neck Carcinoma

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma was developed. After transplantation of KB cells into nude mice, the mice were given tiracoxib, a selective cyclooxygenase (COX)-2 inhibitor, probucol, an antioxidant, and S-1, an oral pro-drug of 5-fluorouracil (5-FU), or combinations of two of them. The combined administration of tiracoxib with probucol significantly inhibited the tumor growth. The angiogenesis in this group was markedly reduced. Tiracoxib and probucol did not affect the intratumoral concentration of 5-FU when coadministered with S-1. The combined use of tiracoxib and probucol is thus a candidate for use in maintenance therapy after the primary therapy for patients with advanced head and neck carcinoma.     

情绪因素及抗焦虑药物对肿瘤休眠及复发的影响

目的 :研究情绪因素以及通过药物控制情绪因素对肿瘤休眠状态的维持与打破及后续复发转移的影响。 方法 :利用肿瘤休眠模型,附加单笼饲养和不定时空瓶刺激联合诱导小鼠产生焦虑、愤怒等应激情绪的小鼠慢性情绪应激模型。通过灌胃给予常规抗焦虑药物地西泮来控制焦虑情绪,探讨情绪及抗焦虑药物对肿瘤休眠状态的维持及防止肿瘤复发的作用。实验分为五组,分别为休眠对照组、单纯给药组、诱导焦虑组、焦虑给药组和外伤刺激组。以500个小鼠乳腺癌细胞Ca761-03接种于小鼠左腿肌肉。休眠对照组、单纯给药组和外伤刺激组常规饲养,其中外伤刺激组在第1个月末切除右爪作为外伤刺激,单纯给药组每天定量灌胃给予地西泮溶液。诱导焦虑组和焦虑给药组以单笼饲养和不定时空瓶刺激联合诱导小鼠产生焦虑、愤怒等应激情绪,其中焦虑给药组每天定量灌胃给予地西泮溶液。连续观察2个月,观察小鼠焦虑情况,观察肿瘤休眠打破(肿瘤发生)及肿瘤转移发生情况。 结果 :各组肿瘤休眠率分别为70%、100%、60%、90%和40%。各组成瘤率分别为30%、0、40%、10%和60%。各组的肺转移率分别为20%、0、30%、0和60%。 结论 :本项研究结果证实,长期负面情绪会促进肿瘤休眠状态的打破,加速肿瘤的生长、复发及转移。抗焦虑药物可以明显减少焦虑行为,并有利于肿瘤休眠状态的维持,减少肿瘤的复发。     

nm23-H1基因对实验性裸鼠肺癌细胞休眠作用的研究

目的:建立人非小细胞肺癌实验性裸鼠肺部的肿瘤细胞休眠模型,并验证nm23-H1基因是否具有促进肿瘤细胞休眠的作用.方法:L9981-nm23-EGFP是nm23-H1基因以真核载体pEGFP质粒转染L998l所构建的人非小细胞肺癌细胞株.L9981-EGFP是转染真核空载体pEGFP质粒的不合nm23-H1基因的人高转移性非小细胞肺癌细胞株.以L9981-nm23-EGFP肺癌细胞作为实验组,空载高转移性肺癌细胞株L9981-EGFP作为对照组,分别接种裸鼠,8周后处死全部裸鼠,检测2组裸鼠肺部肺癌细胞的Ki-67增殖指数,凋亡指数,肿瘤组织VEGF的表达,裸鼠肺组织的调亡指数和G0/G1期细胞占细胞总数的百分比.结果:L9981-nm23-EGFP组免疫组化增殖指数、凋亡指数和VEGF的表达均低于高转移性L9981-EGFP组.流式细胞术检测裸鼠肺组织的凋亡指数亦支持免疫组化的结果.实验组Co/G1期细胞占细胞总数的比率高于对照组.结论:裸鼠肺部有肺癌休眠细胞存在.实验组裸鼠肺部肺癌休眠细胞多于对照组.nm23-H1基因可能具有促进肺癌细胞休眠的作用.     

播散肿瘤细胞的休眠与存活机制及其在防治实体瘤转移中的作用

肿瘤转移的防治可显著改善实体瘤患者的生存,然而目前临床上仍缺乏有效的转移防治药物,其根本原因是现有的干预措施和治疗药物都难以实现对转移的精准防治.由于早期术后患者的转移靶器官中早已存在播散肿瘤细胞(DTCs),这些DTCs难以用现有的影像学技术进行检测,也缺乏有效的干预药物和疗效评估体系,而DTCs一旦生长至影像学可检...     

神经母细胞瘤增殖、凋亡与休眠消退的相关性研究

目的　本实验通过研究神经母细胞瘤的增殖、凋亡的改变 ,结合神经母细胞瘤的分化 ,以探讨增殖、凋亡的改变与神经母细胞瘤休眠消退的关系。方法　肿瘤休眠消退组 :神经母细胞瘤休眠消退 6例 ,男 4例 ,女 2例。取组织制作成石蜡切片 ,运用免疫组织化学方法检测增殖细胞 ,计算增殖细胞占细胞百分比 ,求得增殖指数 (PI)。运用原位DNA末端标记法 ,检测凋亡细胞 ,计算凋亡细胞占细胞百分比 ,求得凋亡指数 (AI)。结果　休眠消退病例中 5例凋亡指数大于 9% ,5例增殖指数大于 13 % ,6例增殖率减凋亡率均小于 4%。结论　增殖指数小于 13 % ,凋亡指数大于 9% ,特别是增殖指数减凋亡指数小于 4% ,神经母细胞瘤休眠消退的可能性大。     

Prevalence of Prostate Cancer Metastases after Intravenous Inoculation Provides Clues into the Molecular Basis of Dormancy in the Bone Marrow Microenvironment

Bone is the preferred metastasis site of advanced prostate cancer (PCa). Using an in vivo murine model of human PCa cell metastasis to bone, we noted that the majority of animals that develop skeletal metastasis have either spinal lesions or lesions in the bones of the hindlimb. Much less frequently, lesions develop in the bones of the forelimb. We therefore speculated whether the environment of the forelimb bones is not permissive for the growth of PCa. Consequently, data on tumor prevalence were normalized to account for the number of PCa cells arriving after intravascular injection, marrow cellularity, and number of hematopoietic stem cell niches. None of these factors were able to account for the observed differences in tumor prevalence. An analysis of differential gene and protein levels identified that growth arrest specific-6 (GAS6) levels were significantly greater in the forelimb versus hindlimb bone marrow. When murine RM1 cells were implanted into subcutaneous spaces in immune competent animals, tumor growth in the GAS6^-/- animals was greater than in GAS6^+/+ wild-type animals. In an osseous environment, the human PC3 cell line grew significantly better in vertebral body transplants (vossicles) derived from GAS6^-/- animals than in vossicles derived from GAS6^+/+ animals. Together, these data suggest that the differences in tumor prevalence after intravascular inoculation are a useful model to study the molecular basis of tumor dormancy. Importantly, these data suggest that therapeutic manipulation of GAS6 levels may prove useful as a therapy for metastatic disease.     

Dose intensity in cancer chemotherapy in gastric cancer

Dose intensity in cancer chemotherapy proposed by Green (1980) and Hryniuk (1984) is a concept of expressing treatments in terms of how much drug is given per unit time (mg/m2/week). It is expected that the dose intensity may clear dose-response relationships which are sometimes obscure in cancer chemotherapy because dose reduction or treatment delay caused by adverse effects. Good correlations between dose intensity and prognosis of cancer patients are observed in breast, lung, ovarian cancer and malignant lymphoma. But only few trials using dose intensity concepts have been performed in chemotherapy for gastric cancer. A randomized controlled trial targeted for dose intensity itself will be necessary to confirm the usefulness of dose intensity concepts.