癌症研究人員可以測定腫瘤細胞基因組的序列,掃描其異常的基因活性,剖析其突變的蛋白質和研究它們在實驗室培養皿中的生長,但研究者一直無法跟蹤細胞形成腫瘤的過程。現在三個獨立研究小組在小鼠體內做到了這一點。他們的研究結果支持這樣的觀點:一小部分細胞驅動腫瘤的生長,而想要治癒癌症可能需要將這些所謂腫瘤幹細胞清除。
目前還無法確認,這些從腦瘤,腸癌和皮膚癌研究的結論是否適用於其他類型腫瘤,但是德克薩斯大學西南醫學中心的路易斯·帕拉達認為,如果它們適用於其他腫瘤,"將深刻地改變目前的化療療效評價和臨床療法的制定標準"。 不僅是看某種療法是否縮小腫瘤,研究人員將更關注是否殺死了正確的細胞。
帕拉達和他的同事們想檢測是否特異性標識健康成人神經幹細胞的一個遺傳標記,也可標識神經母細胞瘤中的癌症幹細胞。他們發現,所有神經母細胞瘤樣本中至少有幾個標記細胞 - 大概是幹細胞。未標記細胞可被標準化療殺死,但腫瘤可迅速恢復。進一步的實驗表明,未標記細胞起源於標記的細胞祖先。當研究者把化療與抑制標記細胞的遺傳手段相結合進行治療時,帕拉達說,腫瘤顯著縮小到"殘留遺蹟"的水平。
在另一項研究中,荷蘭烏得勒支Hubrecht研究所的幹細胞生物學家們把注意力瞄著了腸道。利用藥物驅動的螢光素標誌物表達系統,他們在小鼠體內證實,多種不同類型的腫瘤細胞,其實是來源於同一幹細胞的。而且,這些幹細胞是腫瘤發展的驅動力。
對皮膚癌的研究,Blanpain和他的小組標記單個腫瘤細胞,而不是特異地標記幹細胞。他們發現,細胞表現出兩種不同的分工模式:它們要麼在慢慢耗盡前分裂出少數細胞,或者產生許多細胞。這再次證實,一類獨特的細胞亞群是腫瘤生長的驅動力。
研究者說,下一步的研究計劃將是,搞清楚這些實驗所跟蹤的細胞如何與通過多年移植實驗所確定的,假定的癌症幹細胞相聯繫的。研究人員已經緊鑼密鼓地在尋找殺死這些細胞的方法;現在他們有更多的工具來測試這樣的策略是否會奏效。(生物谷bioon.com)
編譯自:Cancer stem cells tracked
Defining the mode of tumour growth by clonal analysis
Gregory Driessens,Benjamin Beck,Amélie Caauwe,Benjamin D. Simons& Cédric Blanpain
Recent studies using the isolation of a subpopulation of tumour cells followed by their transplantation into immunodeficient mice provide evidence that certain tumours1, 2, including squamous skin tumours3, 4, 5, contain cells with high clonogenic potential that have been referred to as cancer stem cells (CSCs). Until now, CSC properties have only been investigated by transplantation assays, and their existence in unperturbed tumour growth is unproven. Here we make use of clonal analysis of squamous skin tumours using genetic lineage tracing to unravel the mode of tumour growth in vivo in its native environment. To this end, we used a genetic labelling strategy that allows individual tumour cells to be marked and traced over time at different stages of tumour progression. Surprisingly, we found that the majority of labelled tumour cells in benign papilloma have only limited proliferative potential, whereas a fraction has the capacity to persist long term, giving rise to progeny that occupy a significant part of the tumour. As well as confirming the presence of two distinct proliferative cell compartments within the papilloma, mirroring the composition, hierarchy and fate behaviour of normal tissue, quantitative analysis of clonal fate data indicates that the more persistent population has stem-cell-like characteristics and cycles twice per day, whereas the second represents a slower cycling transient population that gives rise to terminally differentiated tumour cells. Such behaviour is shown to be consistent with double-labelling experiments and detailed clonal fate characteristics. By contrast, measurements of clone size and proliferative potential in invasive squamous cell carcinoma show a different pattern of behaviour, consistent with geometric expansion of a single CSC population with limited potential for terminal differentiation. This study presents the first experimental evidence for the existence of CSCs during unperturbed solid tumour growth.
A restricted cell population propagates glioblastoma growth after chemotherapy
Jian Chen,1 Yanjiao Li,1 Tzong-Shiue Yu,1, 2, 4 Renée M. McKay,1 Dennis K. Burns,3 Steven G. Kernie1, 2, 4 & Luis F. Parada1
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year1. This poor prognosis is due to therapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas
Arnout G. Schepers*, Hugo J. Snippert*,?, Daniel E. Stange, Maaike van den Born, Johan H. van Es, Marc van de Wetering, Hans Clevers
The concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted great interest but remains controversial. Studying mouse models, we provide direct, functional evidence for the presence of stem cell activity within primary intestinal adenomas, a precursor to intestinal cancer. By 「lineage retracing」 using the multicolor Cre-reporter R26R-Confetti, we demonstrate that the crypt stem cell marker Lgr5 (leucine-rich repeat–containing heterotrimeric guanine nucleotide–binding protein–coupled receptor 5) also marks a subpopulation of adenoma cells that fuel the growth of established intestinal adenomas. These Lgr5+ cells, which represent about 5 to 10% of the cells in the adenomas, generate additional Lgr5+ cells as well as all other adenoma cell types. The Lgr5+ cells are intermingled with Paneth cells near the adenoma base, a pattern reminiscent of the architecture of the normal crypt niche.