杀灭肿瘤的脂肪干细胞

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斯洛伐克科学院癌症研究所的研究人员最近成功从人类脂肪组织中提取出间充质干细胞（mesenchymal stem cells），并通过基因工程方法使其合成、分泌导向并破坏肿瘤的“自杀基因”。这种基因疗法能够进攻逃避现有检测技术、治疗方法的小肿瘤迁移物。详细内容刊登于7月1日Cancer Research杂志。

  课题负责人Cestmir Altaner博士说，这些脂肪来源的干细胞有望用于以细胞为基础的个性化治疗。每个人都多多少少有些多余的脂肪，脂肪组织也许会成为治疗癌症所需的细胞源。

  间充质干细胞通过更新细胞，修复受损的组织和器官。研究人员发现在混有癌细胞准备向实体肿瘤发展的正常细胞群中也有间充质干细胞，推测这些间充质干细胞会将肿瘤当作受损器官并向肿瘤迁移，因此可被用来寻找原发肿瘤和小的转移瘤。这些干细胞还有一定的可塑性，即能够根据给定组织的微环境发生特化。

  从人类脂肪组织提取出间充质干细胞后，研究人员开始寻找一种比治疗结肠癌标准化疗剂5-fluorouracil (5-FU)对正常细胞毒副作用更小的途径。他们将得到的间充质干细胞在培养基中大量扩增，然后用反转录病毒载体将胞嘧啶脱氨基酶(cytosine deaminase，CD)基因插入细胞的基因组中，这种基因将干细胞中一种毒副作用较小的药物5-fluorocytosine (5-FC)转化为5-FU。接着，研究人员用化疗法杀灭肿瘤，产生一个致死性的旁观者效应（by-stander effect，是指杀肿瘤细胞的导弹，在靶向肿瘤细胞集中营给以杀伤外，也可杀伤一部肿瘤邻近地带的肿瘤细胞）。

  在移植有人类结肠癌的裸鼠（没有免疫功能）中，研究人员首先注射遗传工程得到的间充质干细胞，然后注射5-FC。结果显示，肿瘤生长抑制率达到68.5％，没有一只小鼠出现毒副作用。研究人员说，虽然没有一只小鼠被完全治愈，但我们的程序却非常有效，甚至只用了一次干细胞。很明显，重复治疗效果会更好。

  普通的间充质干细胞有多种来源（比如骨髓）但产量原没有脂肪组织中得到的多。最简单的方法是从切除肿瘤的外科手术中获得脂肪组织，吸脂法也可以用于分离间充质干细胞，这两个过程都比从患者中收集骨髓容易的多。

英文原文：

http://www.aacr.org/home/about-us/news.aspx?d=786

Fat Kills Cancer: Turning Stem Cells Taken from Fat Tissue into Personalized, Cancer-Targeted Therapeutics

July 3, 2007



PHILADELPHIA - Researchers in Slovakia have been able to derive mesenchymal stem cells from human adipose, or fat, tissue and engineer them into \"suicide genes\" that seek out and destroy tumors like tiny homing missiles. This gene therapy approach is a novel way to attack small tumor metastases that evade current detection techniques and treatments, the researchers conclude in the July 1 issue of Cancer Research, a journal of the American Association for Cancer Research.

\"These fat-derived stem cells could be exploited for personalized cell-based therapeutics,\" said the study's lead investigator, Cestmir Altaner, Ph.D., D.Sc., an associate professor in the Cancer Research Institute of the Slovak Academy of Sciences in Bratislava. \"Nearly everyone has some fat tissue they can spare, and this tissue could be a source of cells for cancer treatment that can be adapted into specific vehicles for drug transport.\"

Mesenchymal stem cells help repair damaged tissue and organs by renewing injured cells. They are also found in the mass of normal cells that mix with cancer cells to make up a solid tumor. Researchers believe mesenchymal stem cells \"see\" a tumor as a damaged organ and migrate to it, and so might be utilized as a \"vehicle\" for treatment that can find both primary tumors and small metastases. These stem cells also have some plasticity, which means they can be converted by the micro environment of a given tissue into specialized cells, Altaner says.

After extracting the stem cells from human fat tissue the researchers worked to find a less toxic way to treat colon cancer than the standard-of-care chemotherapy agent, 5-fluorouracil (5-FU), which can produce toxic side effects in normal cells. They expanded the number of mesenchymal stem cells in the laboratory and then used a retrovirus vector to insert the gene cytosine deaminase into the cell. This gene can convert a less toxic drug, 5-fluorocytosine (5-FC), to 5-FU inside the stem cells, and the chemotherapy can then seep out into the tumor, producing a lethal by-stander effect.

In nude mice - animals with an inhibited immune system - engrafted with human colon cancer, the researchers first injected the engineered mesenchymal stem cells, then 5-FC. They found tumor growth was inhibited by up to 68.5 percent in the animals, and none of the mice exhibited any signs of toxic side effects.

However, none of the animals remained tumor-free. \"The procedure was quite effective even though we applied the stem cells just once. Obviously, repeated treatment will increase the efficacy, as would using this strategy in combination with other treatments,\" Altaner said.

Normal mesenchymal cells can be isolated from various sources, including bone marrow, but the yield is not nearly as great as what the researchers derived from fat tissue. Removal of fat tissue during surgery to remove a tumor would be simple, says Altaner. Liposuction could also be used to isolate mesenchymal stem cells can also be gathered and isolated through liposuction, and the cells frozen in liquid nitrogen for future therapeutic use. Both processes would be easier than taking bone marrow from a patient, Altaner said.

The study was funded by grants from the Slovak Academy of Sciences and the League Against Cancer, and support from the Slovakian national cancer genomics program.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.