簡介癌症幹細胞(Cancer Stem Cells) – 魔鬼在細節中(一):定義

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Figure 1 | Models of cancer stem cell evolution: perturbation of the normal differentiation
hierarchy.

這一系列是閱讀此篇論文的摘要和整理:
Valent, P., Bonnet, D., Maria, R.D., Lapidot, T., Copland, M., Melo, J.V., Chomienne, C., Ishikawa, F., Schuringa, J.J., Stassi, G., Huntly, B.J., Herrmann, H.G., Soulier, J.S., Rösch, A., Schuurhuis, G.J., Woehrer, S., Arock, M., Zuber, J., Cerny-Reiterer, S., Johnsen, H.E., Andreeff, M., & Eaves, C.G. (2012). Cancer stem cell definitions and terminology: the devil is in the details. Nature Reviews Cancer, 12, 767-775.

關於“癌症幹細胞(cancer stem cells)”這觀念,如今依舊是討論非常熱烈,姑且不論其實質是否是正確的理論,但這概念在臨床或是研究的應用上卻非常有用,另一方面,癌症幹細胞的定義也隨者時間不段地調整。

Malignant cell populations are organized as unidirectional cellular hierarchies
in which CSCs constitute biologically unique subsets of cells, which are distinguished
from the bulk of the cells that they produce by their exclusive ability to perpetuate the growth of a malignant cell population indefinitely   

— from the paper: (2012). Cancer stem cell definitions and terminology: the devil is in the details. Nature Reviews Cancer, 12, 767-775.

假設惡性腫瘤組織是由少數幾個具有高度自我複製能力的癌細胞所產生,而這群具有自我複製和分化能力的癌症細胞便被稱為癌症幹細胞,在這個理論下,可以用來解釋部分病人的惡性腫瘤在接受治療後,一開始癌細胞數量大減,但一陣子過後復發,反而形成具有抗藥性的癌腫瘤,也就是說這類產生大多數癌組織的“癌症幹細胞”,能將這種抗藥性遺傳給其產生或者說子細胞株。當然,這類對於治療藥物的抵抗性,目前已知也和癌組織和微環境地互動有一定的關係。

這種有少數具由極強自我複製能力的所謂癌症幹細胞,所產生的癌組織,是否一定是符合單向階層(unidirectional hierarchy)關聯,由目前而來的證據,只能說不一定,當組織中有很多癌細胞都具有癌症幹細胞的特性時,有可能此癌症腫瘤組織裡有很多不同種的子細胞株所組成的。與其說是癌症幹細胞是特定類細胞,倒不如說是一種細胞狀態。

關於癌症幹細胞的定義

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再談癌症幹細胞前,先借鑒正常組織中的狀況來論述。

在正常組織中的迭代換新,認為是由少數具有自我複製和分化能力的所謂幹細胞所負責。有趣的是,這些我們定義廣泛具有自我更新特性的幹細胞,實際上在不同的發育階段和位置是非常具有異質性地,這觀念用來反推癌症組織中的“幹細胞”,可見這種的“幹細胞”特性,並非單純只是由單一基因突變或是單純某一過程所產生的。

      Interestingly, it has also become apparent that even stringently defined normal tissue stem cells with extensive self-renewal properties can be intrinsically heterogeneous with regard to their differentiation and self-renewal control in different sites or stages of development .

      Thus, heterogeneity among CSCs in a single tumour type, or even within a single tumour, cannot be assumed to be indicative of an abnormal (tumour-specific) process or to be a consequence of a DNA mutation.

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觀念上的癌症幹細胞定義(Conceptual Context)

惡性前期腫瘤幹細胞(Pre-malignant neoplastic stem cells) 這子類的腫瘤幹細胞可以將腫瘤細胞株持續茁壯,有可能可以再度發展成所謂的癌症幹細胞,但其沒有立即性的癌化驅動潛力。

A subclass of neoplastic stem cells that can propagate neoplastic clones that may or may not develop into cancer-stem cells over time, but have no immediate cancer-initiating potential.

癌症幹細胞(Cancer stem cells)、惡性腫瘤幹細胞(malignant neoplastic stem cells) 這子類的腫瘤幹細胞具有發展成惡性腫瘤細胞株,形成癌症的能力。

A subclass of neoplastic stem cells that propagate malignant clones indefinitely and produce an overt cancer

實驗操作上的癌症幹細胞定義(Operational Context)

體內(in vivo)腫瘤驅動細胞(Neoplasia-initiating cells) 將這類癌腫瘤驅動移植入免疫缺乏的老鼠體內,會形成腫瘤組織,且持續存在。

Cells that regenerate detectable neoplastic populations in xenografted immunodeficient mice that are sustained. usually measured by LDA(limiting diluting assay)

腫瘤或是白血病驅動細胞(Tumour or leukaemia-initiating cells) 將此類腫瘤幹細胞植入免疫缺乏的老鼠,可以產生可檢驗量的癌組織。

A subclass of neoplastic stem cells that regenerate detectable, sustained malignant populations in xenografted immunodeficient mice, usually measured by LDA

腫瘤長期培養驅動細胞(Neoplastic long-term culture-initiating cells) 將此類腫瘤細胞培養在體外環境中,滿足其支持條件,可以包涵惡性前期或是惡性腫瘤細胞。

Cells that can initiate the sustained production of neoplastic populations when cultured in supportive conditions; can include pre-malignant and malignant neoplastic cells, usally measured by LDA

腫瘤球狀細胞(Neoplastic sphere-forming cells) 此類細胞可以在體外培養中,不需依靠環境,形成漂浮組織,且能持續成長。

Cells that can initiate the production of non-adherent ‘sphere’ of neoplastic progeny in in vitro cultures, can include pre-malignant and malignant neoplastic cells, usually measured by counting spheres that can generate secondary spheres when re-plated

這邊比較重要的地方是去假設癌症幹細胞的細胞株係跟正常組織由體幹細胞衍生而成的,有類似,也有相異的地方。

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