Breast cancer tumor in its microenvironment

Credit: National Cancer Institute/Carbone 癌症 Center at the Univ. of Wisconsin

A breast cancer tumor and its microenvironment.

In a breakthrough with important implications for the future of immunotherapy for breast cancer, UC 旧金山 scientists have found that blocking the activity of a single enzyme can prevent a common type of breast cancer from spreading to distant organs.

在研究小鼠模型中,早期阶段的人类乳腺癌的重复键的功能,研究人员发现,一种叫做MMP9普遍存在的酶是癌症的转移促进机制的重要组成部分,有助于创造流动癌细胞形成好客的环境新的转移性肿瘤。

“Metastasis is the biggest hurdle when it comes to successfully treating breast cancer, and solid tumors in general,” said 薇薇Plaks 500 Internal Server Error

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 泽娜·韦布, Ph.D., a professor of anatomy and associate director for basic science at the UCSF Helen Diller Family Comprehensive 癌症 Center.

他们检查了,当他们在小鼠模型中他们的肺组织,MMP9的研究人员发现,在健康组织重塑和它转化成一种避风港的迁移乳腺癌细胞参与。当癌细胞定植这些网站与MMP9的帮助下,他们能够开始生长成新的肿瘤。

The new study, published Nov. 14 in the journal Life Science Alliance,这可以停止这些转移表明,他们能够打好前肿瘤生长的基础。通过施用抗体靶向并破坏其特异性MMP9活性,科学家们能够预防癌症的定殖小鼠的肺。但有趣的是,干扰随着MMP-9 ADH没有影响原发肿瘤,这表明酶的主要作用在这种情况下帮助为肾癌和殖民现有恶性肿瘤等器官,而不是建立促进原发肿瘤的生长。     

在这项研究之前,Werb和其他人发现,MMP9扮演重塑细胞外基质(ECM)的重要作用 - 生物分子拼凑而成的发现,提供结构和形状的器官细胞外,帮助细胞沟通彼此,并建立微环境,促进细胞健康,性传播疾病在许多其他功能。 ,虽然MMP9被称为癌症参与,特别是在重塑ECM打造利基肿瘤恶性肿瘤是热情好客于ITS在转移的早期阶段的作用已经没有充分的探讨。

“,审查大量的转移性乳腺癌的形成利基研究主要集中对晚期癌症,肿瘤是相当当的进展。什么套与众不同的是我们的研究中,我们选择了焦点上早于改变肿瘤微环境和转移过程。 ESTA使我们能够接近MMP9这剧真的很重要的早期阶段,“这项新研究的马克说owyong,共同第一作者用 乔纳森·宙, M.D., Ph.D., a clinical fellow in the UCSF School of 医学. Owyong, Chou and Plaks conducted the research as members of the Werb lab. 

The first hint that MMP9 might be involved in early-stage metastasis came from publicly available gene expression data from clinical breast cancer biopsies. While sifting through this data, the researchers noticed that MMP9 levels were elevated in metastatic disease. 

进一步调查MMP9在转移中的作用,研究人员转向“管腔B”乳腺癌,这是在本病的最常见的诊断形式的独特的小鼠模型。 “捕获乳腺癌的进展自然,密切模仿病人经历了疾病的进展,因为我们选择的模型是为数不多的” owyong说。 

在实验一键设置,将肿瘤细胞注射入研究者小鼠HAD早期乳腺癌转移,但没有明显的。他们发现这些细胞殖民肺部肿瘤生长形成新的网站。这些细胞但被当注射到小鼠中没有乳腺癌遗传上相同,没有转移灶形成。

当实验中的小鼠中重复早期乳腺癌基因MMP9谁被打掉,有转移性肺肿瘤的尺寸的减少显著,虽然有对原发性乳腺肿瘤组织没有影响。这些结果表明,MMP9需要促进转移,但对于原发肿瘤继续生长不是必需的。

“This was a very promising result and suggests that a therapeutic paradigm focused on intercepting metastasis early might offer a new route for treating certain kinds of breast cancer.”
薇薇Plaks博士

类似的结果被视为研究人员在MMP9的活性被破坏了一个独特的抗体靶向酶的活化具体为形式。研究者注射细胞到肿瘤这些小鼠,随后通过抗体的注射每两天。在治疗方案结束后,老鼠和被视察研究人员发现在数量和小鼠肺转移世卫组织收到的抗体与那些没有比较的大小显著减少。

“This was a very promising result and suggests that a therapeutic paradigm focused on intercepting metastasis early might offer a new route for treating certain kinds of breast cancer,” said Plaks.

The researchers also discovered that interfering with MMP9 activity helped recruit and activate cancer-fighting immune cells to metastatic sites, a result with important implications for treating certain types of metastatic breast cancer with immunotherapy.

免疫疗法通过争取机体的免疫系统来杀死癌细胞,并找到工作。某些癌症,但 - 包括管腔乳腺癌B,新研究的主要焦点 - 不屈服于免疫治疗。据Plaks,这是因为,除了在转移他们的成长直接影响,MMP9也是在重塑ECM和建设中发挥着重要的作用网格状围绕转移部位的帮助障碍排除免疫细胞。 ESTA可以解释为什么一些转移性癌细胞能够逃避免疫疗法通过猛攻触发的免疫。

But the new study shows that when MMP9 is incapacitated, metastatic sites may no longer be able to keep immune cells at bay. Plaks thinks that this represents an important step towards making breast cancer more susceptible to immunotherapies that have proven effective against other forms of cancer.

“这些发现是在癌症免疫学一个激动人心的时刻,用抗体靶向MMP9正在探索临床使用积极在生物技术产业,” Plaks说。 “有许多人在试图利用免疫疗法治疗管腔b型转移性乳癌极大的兴趣,但到目前为止,成功-受到限​​制。我们的工作表明,免疫治疗与MMP9活性靶向抗体的组合方式实际上可能会取得成功。“

作者: Additional authors include Renske JE van den Bijgaart, Niwen Kong, Gizem Efe, Carrie Maynard, Charlotte Koopman, Elin Hadler-Olsen, Mark Headley, Charlene Lin and Chih-Yang Wang from UCSF, and Dalit Talmi-Frank and Inna Solomonov from the Weizmann Institute of Science.

资金: This study was supported by a Department of Defense Postdoctoral Fellowship, National Cancer Institute grants R01 CA057621 and U01 CA199315, the Parker Institute for 癌症 Immuno- therapy and funds from the Israel Science Foundation.

信息披露: The authors declare that they have no conflict of interest.