生物谷：腫瘤干細胞啟動,、促使癌細胞生長的理論現(xiàn)已成為臨床和基礎研究領域的主流觀點。最近有研究不僅鑒別出腫瘤干細胞,，而且還證實了如果將腫瘤干細胞移植到第二中間宿主后會引發(fā)腫瘤,。但目前研究者們對當初干細胞是如何突變并引發(fā)原發(fā)性腫瘤的過程仍不清楚,。
美國國家科學院院刊 (Proceedings of the National Academy)最新一期的一份研究報告指出,，利用注射單一細胞的方法,，能夠誘導乳房發(fā)展出腫瘤組織,，為單一細胞啟動癌癥的腫瘤干細胞模型提供了新的證據(jù),。
傳統(tǒng)的理論認為，腫瘤組織之所以擴大,，并非單一細胞發(fā)生癌變所致,，應該是腫瘤發(fā)生處的組織環(huán)境，提供了復雜的細胞環(huán)境,，因此腫瘤組織得以擴大,。在這種傳統(tǒng)的理論的指導下，無法對細胞的癌變過程作出細致的研究,，所以并未發(fā)展出治療癌癥的新方法,。
這項研究由沙克研究所 (Salk Institute)曾獲得諾貝爾獎的 Renato Dulbecco博士領導。研究人員將細胞株 LA7,，注射到NOD-SCID裸鼠乳房組織中,，結(jié)果成功的從注射進去的單一細胞，發(fā)展成為新的乳腺癌腫瘤。實驗結(jié)果顯示,，即使只注射一個LA7細胞,，9只裸鼠中也有7只產(chǎn)生了腫瘤（67%）。
這個成功的腫瘤模型,，為腫瘤干細胞理論提供了新的證據(jù),，即即使只有單一細胞發(fā)生癌變，也會誘導出整個腫瘤組織的生長,。單一細胞變化的過程,，作為癌癥研究的新切入點，為腫瘤的治療提供了新的研究策略,。（援引生命經(jīng)緯）
原始出處:
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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