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【medical-news】NIH：降低胰腺肿瘤防御能力的新方法

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NIH Research Matters

April 4, 2011

Breaking Down Pancreatic Tumor Defenses
A new approach for attacking pancreatic tumors may lead to improved therapy for patients with inoperable disease, scientists report. The strategy offers hope for more effective techniques to eliminate tumors.

Macrophages (the small round cells) attacking a cancer cell. Image by Dr. Raowf Guirguis, NCI.
Pancreatic cancer is one of the most deadly types of cancer, especially in the later stages. More than 40,000 new cases are diagnosed nationwide every year. Most diagnoses are made once the cancer has already spread, making successful treatment nearly impossible. A major challenge in treating pancreatic tumors is overcoming their ability to force immune cells to tolerate and even support their growth.

A team of researchers at the University of Pennsylvania led by Dr. Gregory Beatty, Dr. Peter O'Dwyer and Dr. Robert Vonderheide tried a new approach to break down the tumors' defenses. They predicted that the immune system's T cells could be turned on by using an antibody to a cell-surface molecule called CD40, which controls the cells' activation. Having overcome the tumors' suppression, the T cells would then attack and kill the tumors. While the treatment proved effective in some patients, the reason was a surprise. The study was partially funded by NIH's National Cancer Institute (NCI) and appeared in the March 25, 2011, issue of Science.

The team first tested a combination treatment in pancreatic cancer patients who couldn’t be cured by surgery. The scientists administered a standard drug, gemcitabine, along with the CD40 antibody. The results were promising. CT scans showed that tumors shrank in 4 out of 21 patients, and average patient survival was longer than usually seen with gemcitabine alone. The team examined samples from the tumors after treatment, expecting to see T cells. Surprisingly, they didn't; rather, another type of immune cell, the macrophage, dominated the tumors. Macrophages are known to be activated by binding CD40 on other immune cells, but they weren't thought to be involved in fighting tumors.

To further investigate, the team used a genetically engineered mouse strain that develops pancreatic cancer spontaneously. After treatment with gemcitabine and CD40 antibody, the tumors shrank in 30% of the animals. As in the humans, the T cells weren't necessary for the shrinkage, and gemcitabine alone couldn't cause it.

When the researchers depleted macrophages from the mice, the tumors didn’t shrink with CD40 antibody treatment. Moreover, when the scientists cultured tumor cells with macrophages from the pancreas of treated animals, the macrophages proved to be effective cell killers. This suggested that the antibody treatment had overcome the tumor’s ability to suppress the macrophages. The team observed that the treatment caused the thick network of connective tissue around the tumors, called the stroma, to disintegrate. When they depleted macrophages again, the stroma stayed intact.

"Until this research, we thought the immune system needed to attack the cancer directly in order to be effective," explains Vonderheide. "Now we know that isn’t necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumors fell apart as a result of that assault."

—by Allison Bierly, Ph.D.

Related Links:

Pancreatic Cancer:
http://www.cancer.gov/cancertopics/types/pancreatic
Targeted Immunotherapies:
http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/htmlcourse/page4

http://www.nih.gov/researchmatters/april2011/04042011pancreatic.htm

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2011-04-07 09:15 浏览 : 615 回复 : 1

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NIH Research Matters
NIH研究项目

April 4, 2011
2011年4月4日

Breaking Down Pancreatic Tumor Defenses
破坏胰腺肿瘤防御能力
A new approach for attacking pancreatic tumors may lead to improved therapy for patients with inoperable disease, scientists report. The strategy offers hope for more effective techniques to eliminate tumors.
科学家发现，一项攻击胰腺肿瘤的新方法可以提高无法接受手术胰腺肿瘤患者的治疗效果。这项策略为更有效消除肿瘤的技术提供了希望。

Macrophages (the small round cells) attacking a cancer cell. Image by Dr. Raowf Guirguis, NCI.
正在攻击癌症细胞的巨噬细胞（小圆细胞）。国立癌症研究所Raowf Guirguis博士拍摄。

Pancreatic cancer is one of the most deadly types of cancer, especially in the later stages. More than 40,000 new cases are diagnosed nationwide every year. Most diagnoses are made once the cancer has already spread, making successful treatment nearly impossible. A major challenge in treating pancreatic tumors is overcoming their ability to force immune cells to tolerate and even support their growth.
胰腺癌，尤其到了晚期，是致死率最高的癌症之一。每年，美国有4万新诊断出的胰腺癌病例，这些病例大多数在被诊断出时癌症已经扩散，几乎无法成功治疗。治疗胰腺肿瘤一项重要的挑战是如何来克服这些肿瘤使免疫细胞耐受甚至支持肿瘤生长的能力。

A team of researchers at the University of Pennsylvania led by Dr. Gregory Beatty, Dr. Peter O'Dwyer and Dr. Robert Vonderheide tried a new approach to break down the tumors' defenses. They predicted that the immune system's T cells could be turned on by using an antibody to a cell-surface molecule called CD40, which controls the cells' activation. Having overcome the tumors' suppression, the T cells would then attack and kill the tumors. While the treatment proved effective in some patients, the reason was a surprise. The study was partially funded by NIH's National Cancer Institute (NCI) and appeared in the March 25, 2011, issue of Science.
由Gregory Beatty博士、Peter O'Dwyer博士和Robert Vonderheide博士领衔的宾夕法尼亚大学的研究团队尝试采用一种新的方法来破坏肿瘤的防御能力。他们预测，采用控制细胞激活的细胞表面分子CD40的抗体，可以激活免疫系统中的T细胞。如果能克服肿瘤细胞的抑制作用，T细胞就可以进攻并杀死这些肿瘤。尽管CD40抗体治疗已在一些患者中取得了一定的成效，但是这种药物起效的激励却出人意料。这项研究得到了NIH所属国立癌症研究所的部分资助，结果发表在2011年3月25日出版的Science杂志上。

The team first tested a combination treatment in pancreatic cancer patients who couldn’t be cured by surgery. The scientists administered a standard drug, gemcitabine, along with the CD40 antibody. The results were promising. CT scans showed that tumors shrank in 4 out of 21 patients, and average patient survival was longer than usually seen with gemcitabine alone. The team examined samples from the tumors after treatment, expecting to see T cells. Surprisingly, they didn't; rather, another type of immune cell, the macrophage, dominated the tumors. Macrophages are known to be activated by binding CD40 on other immune cells, but they weren't thought to be involved in fighting tumors.
研究团队首先考察了对无法采用手术治愈的胰腺癌患者进行联合治疗的效果，给予标准治疗药物吉西他滨以及CD40抗体。结果比较看好，CT扫描显示21个患者有4个出现瘤体缩小，平均患者生存率也长于只接受吉西他滨治疗的患者。研究团队检测了治疗后的肿瘤样品，希望能检测到T细胞。令人惊奇的是，他们并没有发现T细胞，而是发现另一种免疫细胞，巨噬细胞，占满了整个瘤体。尽管此前已知CD40和其它免疫细胞结合时会激活巨噬细胞，但是科学家还没有想过巨噬细胞也会参与杀灭肿瘤细胞。

To further investigate, the team used a genetically engineered mouse strain that develops pancreatic cancer spontaneously. After treatment with gemcitabine and CD40 antibody, the tumors shrank in 30% of the animals. As in the humans, the T cells weren't necessary for the shrinkage, and gemcitabine alone couldn't cause it.
为进一步进行观察，研究人员采用基因工程小鼠原发性胰腺癌模型进行了考察。采用吉西他滨和CD40抗体治疗后，30%的小鼠肿瘤瘤体缩小。和在人类中一样，T细胞并不是瘤体缩小的必要因素，单独使用吉西他滨也不会导致肿瘤瘤体缩小。

When the researchers depleted macrophages from the mice, the tumors didn’t shrink with CD40 antibody treatment. Moreover, when the scientists cultured tumor cells with macrophages from the pancreas of treated animals, the macrophages proved to be effective cell killers. This suggested that the antibody treatment had overcome the tumor’s ability to suppress the macrophages. The team observed that the treatment caused the thick network of connective tissue around the tumors, called the stroma, to disintegrate. When they depleted macrophages again, the stroma stayed intact.
当研究人员采用方法耗尽小鼠的巨噬细胞后，采用CD40抗体治疗肿瘤瘤体并不缩小。而且，研究人员将肿瘤细胞和从这些小鼠胰腺分离的巨噬细胞共同培养时，发现这些巨噬细胞可以有效杀死肿瘤细胞。表明CD40抗体治疗可以克服肿瘤对巨噬细胞的抑制能力。研究人员还发现CD40药物治疗可以破坏肿瘤周围结缔组织网架部分（间质部分）。当巨噬细胞被耗尽时，CD40治疗后间质部分保持完好无损。

"Until this research, we thought the immune system needed to attack the cancer directly in order to be effective," explains Vonderheide. "Now we know that isn’t necessarily so. Attacking the dense tissues surrounding the cancer is another approach, similar to attacking a brick wall by dissolving the mortar in the wall. Ultimately, the immune system was able to eat away at this tissue surrounding the cancer, and the tumors fell apart as a result of that assault."
Vonderheide博士解释说：“在这项研究之前，我们一直都认为CD40抗体治疗依赖的是免疫系统对肿瘤进行的直接攻击，现在我们知道这并非是必要的。就像在通过化解墙上的砂浆对砖头墙壁进行攻击原理一样，攻击肿瘤周围的密集组织也是一种治疗肿瘤有效的途径。最后，免疫系统可以吃掉这些肿瘤周围的组织，导致肿瘤细胞最终被破坏。”

—by Allison Bierly, Ph.D.
--- 本文由Allison Bierly博士报道。

Related Links:
相关链接

Pancreatic Cancer:
胰腺癌：
http://www.cancer.gov/cancertopics/types/pancreatic
Targeted Immunotherapies:
靶向免疫治疗：
http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/htmlcourse/page4

重新整理后为（共1055中文字）：

NIH研究项目

2011年4月4日

破坏胰腺肿瘤防御能力

科学家发现，一项攻击胰腺肿瘤的新方法可以提高无法接受手术胰腺肿瘤患者的治疗效果。这项策略为更有效消除肿瘤的技术提供了希望。

正在攻击癌症细胞的巨噬细胞（小圆细胞）。国立癌症研究所Raowf Guirguis博士拍摄。

胰腺癌，尤其到了晚期，是致死率最高的癌症之一。每年，美国有4万新诊断出的胰腺癌病例，这些病例大多数在被诊断出时癌症已经扩散，几乎无法成功治疗。治疗胰腺肿瘤一项重要的挑战是如何来克服这些肿瘤使免疫细胞耐受甚至支持肿瘤生长的能力。

由Gregory Beatty博士、Peter O'Dwyer博士和Robert Vonderheide博士领衔的宾夕法尼亚大学的研究团队尝试采用一种新的方法来破坏肿瘤的防御能力。他们预测，采用控制细胞激活的细胞表面分子CD40的抗体，可以激活免疫系统中的T细胞。如果能克服肿瘤细胞的抑制作用，T细胞就可以进攻并杀死这些肿瘤。尽管CD40抗体治疗已在一些患者中取得了一定的成效，但是这种药物起效的激励却出人意料。这项研究得到了NIH所属国立癌症研究所的部分资助，结果发表在2011年3月25日出版的Science杂志上。

研究团队首先考察了对无法采用手术治愈的胰腺癌患者进行联合治疗的效果，给予标准治疗药物吉西他滨以及CD40抗体。结果比较看好，CT扫描显示21个患者有4个出现瘤体缩小，平均患者生存率也长于只接受吉西他滨治疗的患者。研究团队检测了治疗后的肿瘤样品，希望能检测到T细胞。令人惊奇的是，他们并没有发现T细胞，而是发现另一种免疫细胞，巨噬细胞，占满了整个瘤体。尽管此前已知CD40和其它免疫细胞结合时会激活巨噬细胞，但是科学家还没有想过巨噬细胞也会参与杀灭肿瘤细胞。

为进一步进行观察，研究人员采用基因工程小鼠原发性胰腺癌模型进行了考察。采用吉西他滨和CD40抗体治疗后，30%的小鼠肿瘤瘤体缩小。和在人类中一样，T细胞并不是瘤体缩小的必要因素，单独使用吉西他滨也不会导致肿瘤瘤体缩小。

当研究人员采用方法耗尽小鼠的巨噬细胞后，采用CD40抗体治疗肿瘤瘤体并不缩小。而且，研究人员将肿瘤细胞和从这些小鼠胰腺分离的巨噬细胞共同培养时，发现这些巨噬细胞可以有效杀死肿瘤细胞。表明CD40抗体治疗可以克服肿瘤对巨噬细胞的抑制能力。研究人员还发现CD40药物治疗可以破坏肿瘤周围结缔组织网架部分（间质部分）。当巨噬细胞被耗尽时，CD40治疗后间质部分保持完好无损。

Vonderheide博士解释说：“在这项研究之前，我们一直都认为CD40抗体治疗依赖的是免疫系统对肿瘤进行的直接攻击，现在我们知道这并非是必要的。就像在通过化解墙上的砂浆对砖头墙壁进行攻击原理一样，攻击肿瘤周围的密集组织也是一种治疗肿瘤有效的途径。最后，免疫系统可以吃掉这些肿瘤周围的组织，导致肿瘤细胞最终被破坏。”

--- 本文由Allison Bierly博士报道。

相关链接：

胰腺癌：
http://www.cancer.gov/cancertopics/types/pancreatic
靶向免疫治疗：
http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/htmlcourse/page4

2011-04-07 10:56

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