学者“炮轰”癌症干细胞理论

　　

生物通报道，癌症干细胞无疑是癌症学说理论中的重要课题，对于癌症干细胞的研究都基于15年前，一名来自多伦多大学的分子生物学家John Dick首次发现了癌症干细胞，时隔多年，癌症干细胞这一名词甚至理论遭受学者们的质疑，究竟有没有癌症干细胞，癌症干细胞难道是个天大的谎言。

 

癌症干细胞理论启蒙

15年前，多伦多大学的分子生物学家John Dick在做实验的时候发现，并不是所有的癌症干细胞都是经历相同的步骤发展而来的。尤其是，只有小部分的具有自我更新能力的白血病细胞能发展成肿瘤，因此John Dick将这些能发育成肿瘤的变异细胞称为癌症干细胞（Cancer Stem Cells，CSCs）。于是，癌症研究领域升起一颗闪亮的明星，癌症干细胞。无数的学者顺着这一思路期盼能找到只针对癌症干细胞的药物治愈癌症。

 

癌症干细胞理论模型建立

2003年癌症干细胞理论的模型正式建立，由来自密歇根大学的Michael Clarke, Max Wicga，Sean Morrison等人首次建立。他们首次在乳腺癌组织中发现存在癌性的干细胞样细胞群，这是第一次证实存在有癌症干细胞。从那以后，各种癌症干细胞闪亮登场，人们在越来越多的肿瘤中发现有癌细胞的存在，包括，肺癌，脑癌，结肠癌和胰腺癌等。Wicha说，这一盛况完全记录在当时的顶级刊物上，翻阅一下当年的几大科学期刊哪都有癌症干细胞的踪影。

 

质疑声起

至2007年，癌症干细胞的理论逐步完善，直到一个来自哈佛大学大学医学院和Dana-Farber癌症研究所的研究团队提出质疑。该团队由Kornelia Polyak带领，他们深入的研究了密歇根大学研究团队的发现。当时，Polyak等人的文章成为当月最热门的文章（M. Shipitsin et al., "Molecular definition of breast tumor heterogeneity," Cancer Cell, 11:259-73, 2007. (Cited in 95 papers)），他们将密歇根大学的科学家推测为乳腺癌症干细胞的细胞与其他一些分化程度更高的癌细胞进行对比，结果发现两种细胞间存在好几处遗传差异。这些结果不禁让哈佛的科学家怀疑，这些癌细胞其实并不来自癌症干细胞，它们各有各的祖细胞。

 

Polyak认为，癌细胞发生遗传变异达到改变靶位的目的，癌细胞不是来自同一个克隆细胞系，有可能是正常的细胞突变成癌性细胞，这些癌性细胞的子代细胞又再度发生突变，产生更多遗传特征各异的癌性细胞。这也就解释了为什么以癌症干细胞为指导方针的治疗方案总是不成功，原因就在癌细胞是不断突变产生新的肿瘤，每个癌细胞的子代细胞都发生突变以确保癌细胞逃避药物和免疫系统的攻击，因此说，癌细胞并不是来自同一个癌症干细胞克隆群，而是个个不同，就像世界上没有两片相同的叶子一样。

 

其他专家学者的意见

尽管Polyak的文章在业界十分的流行，很多人都愿意接受这一新的理论。但是也有些学者认为癌症干细胞的理论仍是对的，只是随着研究的深入发现的问题越来越多，这一理论必须不断更新修改，不过这并不影响癌症干细胞理论的存在。

（生物通 小茜）

 

More Details

From stem to stern

Despite the popularity of Polyak's paper, most researchers continue to believe the CSC hypothesis, though they acknowledge it may need some fine-tuning. "This so-called distinction between the two models of carcinogenesis is really a false dichotomy," says Wicha. "It's not all or none—there are parts of both [models] that are really correct."

 

"There's nothing about the cancer stem cell hypothesis that would preclude cells changing over time within the tumor," says Michael Lewis, a developmental biologist at Baylor College of Medicine in Houston, Texas. Indeed, Dick showed that CSCs in leukemia also mutate during disease progression, 3  which can potentially give rise to more aggressive tumorigenic cells. "Cancer stem cells themselves aren't a homogeneous entity and they can evolve," Dick says.

 

The hierarchical CSC model also generally assumes that the ruling CSCs are vanishingly rare. Yet a recent study casts doubt on this prediction, as well. Last December, Morrison found that the number of tumor-initiating cells in human melanoma was about one in four in severely immune-compromised mice, compared to about one in a million as previously observed in standard assays. 4  "Melanoma is not following a cancer stem-cell model, at least not in the way the model has been formulated so far," says Morrison.

 

Rarity, however, is beside the point, notes Lewis. "The relative frequency of [CSCs] can't be one of the criteria by which you assess if cells are cancer stem cells or not," he says. Instead, one needs to test for a subpopulation—no matter how frequent—that can reform tumors and is resistant to standard cancer treatments, he argues.

 

Notably, Baylor oncologist Jenny Chang, together with her colleague Jeffrey Rosen, compared breast tumors in patients before and after chemotherapy, and found a three-fold enrichment in cells resembling CSCs following treatment, signifying that tumorigenic cells are, indeed, more resilient. 5  "There are different subpopulations of [cancer] cells that we need to target separately," says Chang. These results lend credibility to the CSC hypothesis where it really counts, adds Wicha. "It's a valid model because it actually predicts behavior in the clinic," he says.

 

 

Fashioning a model

The root cause of cancer remains fuzzy in part because the methods used to find the cells capable of regenerating tumors are flawed, says William Kaelin, a cancer geneticist at the Dana-Farber Cancer Institute. "I'm definitely worried about the bioassays that we're using," because they involve injecting human cells into immune-compromised mice. In response, several researchers, including Jane Visvader of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, are now turning to syngeneic mouse models of human breast and other cancers. "There is no doubt that the xenotransplantation system is far from perfect," Visvader says.

 

Last year, Visvader, Clarke, and Rosen all independently found evidence of CSCs in various mouse models of breast cancer. These studies "argue pretty strongly that it's a subset of the cells that are responsible for initiating tumor growth," says Lewis. Visvader, however, only found CSC markers in two of the three mouse models she tested. 6   "Some, but not all, models of mammary tumorigenesis seem to be driven by cancer stem cell propagation," she notes.

 

Michail Shipitsin, the Hot Paper's first author, agrees. "Every cancer case is somewhat unique," he says. The CSC hypothesis may be relevant for some tumors, but "at this point it's unclear" if it applies to breast cancer. "There's a lack of data to support one opinion or the other," he says.

 

"Like all good things in science, I suspect that the rigid version of the cancer stem cell model is going to need some tweaking," says Dick. "It'll be interesting times to see what the data holds."