PNAS：单个细胞诱导出乳腺癌的肿瘤模型
生物谷：肿瘤干细胞启动、促使癌细胞生长的理论现已成为临床和基础研究领域的主流观点。最近有研究不仅鉴别出肿瘤干细胞，而且还证实了如果将肿瘤干细胞移植到第二中间宿主后会引发肿瘤。但目前研究者们对当初干细胞是如何突变并引发原发性肿瘤的过程仍不清楚。
美国国家科学院院刊 (Proceedings of the National Academy)最新一期的一份研究报告指出，利用注射单一细胞的方法，能够诱导乳房发展出肿瘤组织，为单一细胞启动癌症的肿瘤干细胞模型提供了新的证据。
传统的理论认为，肿瘤组织之所以扩大，并非单一细胞发生癌变所致，应该是肿瘤发生处的组织环境，提供了复杂的细胞环境，因此肿瘤组织得以扩大。在这种传统的理论的指导下，无法对细胞的癌变过程作出细致的研究，所以并未发展出治疗癌症的新方法。
这项研究由沙克研究所 (Salk Institute)曾获得诺贝尔奖的 Renato Dulbecco博士领导。研究人员将细胞株 LA7，注射到NOD-SCID裸鼠乳房组织中，结果成功的从注射进去的单一细胞，发展成为新的乳腺癌肿瘤。实验结果显示，即使只注射一个LA7细胞，9只裸鼠中也有7只产生了肿瘤（67%）。
这个成功的肿瘤模型，为肿瘤干细胞理论提供了新的证据，即即使只有单一细胞发生癌变，也会诱导出整个肿瘤组织的生长。单一细胞变化的过程，作为癌症研究的新切入点，为肿瘤的治疗提供了新的研究策略。（援引生命经纬）
原始出处:
Published online before print June 12, 2007, 10.1073/pnas.0703071104
PNAS | June 19, 2007 | vol. 104 | no. 25 | 10476-10481
BIOLOGICAL SCIENCES / CELL BIOLOGY
The properties of a mammary gland cancer stem cell
I. Zucchi*,
, S. Sanzone*, S. Astigiano
, P. Pelucchi*, M. Scotti*, V. Valsecchi*, O. Barbieri,
, G. Bertoli*, A. Albertini*, R. A. Reinbold¶, and R. Dulbecco,||
*Institute of Biomedical Technologies, National Research Council, Via Cervi 93, 20090 Segrate-Milan, Italy; Istituto Scientifico per lo Studio e la Cura dei Tumori, Largo Benzi 10, 16132 Genoa, Italy; Dipartimento di Medicina Sperimentale, Università di Genova, Largo Benzi 10, 16132 Genoa, Italy; ¶Max Planck Institute, D48149 Muenster, Germany; and ||The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037
Contributed by R. Dulbecco, April 5, 2007 (received for review March 1, 2007)
The cancer stem cell hypothesis posits that tumors are derived from a single cancer-initiating cell with stem cell properties. The task of identifying and characterizing a single cancer-initiating cell with stem cell properties has proven technically difficult because of the scarcity of the cancer stem cells in the tissue of origin and the lack of specific markers for cancer stem cells. Here we show that a single LA7 cell derived from rat mammary adenocarcinoma has the following properties: the differentiation potential to generate all of the cell lineages of the mammary gland; the ability to generate branched duct-like structures that recapitulate morphologically and functionally the ductal–alveolar-like architecture of the mammary tree; and the capacity to initiate heterogeneous tumors in nonobese diabetic-SCID mice. In addition, we show that cultured cells derived from tumors generated by a single LA7 cell-injection have properties similar to LA7 cells, can generate all of the cell lineages of the mammary gland, and recapitulate the ductal–alveolar-like architecture of the mammary tree. The properties of self-renewal, extensive capacity for proliferation, multilineage differentiation potential, and single-cell tumor-initiation potential suggest that LA7 cells are cancer stem cells and can be used as a model system to study the dynamics of tumor formation at the single-cell level.
p21/WAF1 | mammary gland differentiation | single cell injection
Fig. 1. Analysis of mammospheres generated by LA7 cells. (A) Self-renewing mammospheres generated by LA7 cells at passages 8 (p8) and 47 (p47). (Magnification: p8, x20; p47, x32.) (B) Mammosphere from a single LA7 cell at passage 13 (d0), plated onto collagen over a 10-day time period, generates morphologically differentiated cells (d1–d9) and forms tubular-like structures at days 5–9 (d5–d9, red arrowheads). (Magnification: d0, x40; d1 and d3, x20; d5, d7, and d9, x10.) (C) Mammosphere-generated outgrowths on collagen express K18. (C1–C3) Images show K18 staining on cells derived from the disaggregated mammosphere before outgrowth generation (C1), a mammosphere outgrowth generated from a single LA7 cell at passage 13 (C2), and a mammosphere outgrowth generated from a single LA7 cell at passage 36 (C3). (C4) A negative control stained using the secondary antibody only. (Magnification: x40.) Specifically, a single outgrowth from a single-cell-generated mammosphere was sectioned into portions, and individual portions were used for marker expression analysis for C2–C4 and D2–D4 and for E (lane 2). (D) Mammosphere-generated outgrowths on collagen express K14. Shown is K14 staining on cells derived from the disaggregated mammosphere before outgrowth generation (D1), a section of the mammosphere outgrowth generated from a single LA7 cell at passage 13 (D2), and a section of the mammosphere outgrowth generated from a single LA7 cell at passage 36 (D3). (D4) A negative control stained with the secondary antibody only. (Magnification: D2, x32; D1, D3, and D4, x40.) (E) Mammosphere-generated outgrowths express 
-casein. After incubation using lactogenic hormones, the remaining portion of the 10-day outgrowth at early passage, used in Fig. 2 C and D, was used to test for the expression of -casein with Western blot analysis. Lanes: 1, Cells derived from mammospheres; 2, outgrowth from a mammosphere at passage 13 after hormone induction; 3, outgrowth from a mammosphere at passage 13 without induction.
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