确认黑色素瘤抑制剂


  April 3, 2009 — 国家健康研究中心(NIH)的研究者确认了一种可以抑制黑色素瘤的基因。在线发表于3月29日Nature Genetics期刊的一篇研究写道,此基因称为「基质金属蛋白酵素-8(MMP8)」,可供作为黑色素瘤的新个人化治疗。
  
  这项新发现也让人可以理解,曾被视为有效的抗癌制剂、MMP抑制剂,为什么在临床上是令人失望的。
  
  国家人类基因组图研究中心(NHGRI)的Lavanya H. Palavalli医师领导的研究者解释,MMP是降解细胞成分的酵素,包括细胞外基质。这些酵素帮助身体蛋白质分解与再度循环,因此在晒伤、切割伤或其它伤害后的皮肤重组过程扮演重要角色。
  
  MMP8是23种MMP基因之一。研究者表示,已知这一群基因与癌症转移有关。
  
  MMP基因突变被视为致癌基因,或者促进癌细胞生长。因此,使用MMP抑制剂抑制MMP活性是肿瘤研究与药物研发的焦点。研究者指出,对MMP的研究已有数十年,但它已经证明是不成功的。作者写道,使用这些抑制剂的临床试验显示没有效果,且偶尔会加速肿瘤生长。
  
  新的NIH研究暗示何以MMP抑制剂与MMP抑制有问题,何以MMP8 对黑色素瘤抑制有用。
  
  透过一系列的实验,NIH研究者发现,人类黑色素肿瘤细胞是野生型的、正常的MMP8 — 也就是没有突变的MMP8,可以抑制那些黑色素瘤细胞生长。因此,抑制某些(野生型)MMP8 基因可抑制黑色素瘤细胞生长。
  
  作者之一认为,此发现与对癌症分子的理解一致。
  
  资深研究作者Yardena Samuels博士在声明中表示,我们通常将癌症视为一种疾病,癌症也确实有很多共同起源。但是当我们就DNA观点讨论时,发现不同的癌症有不同的基因资料,所以不同的病患会有同样的癌症。她是NHGRI内部研究小组癌症基因组的研究员。
  
  研究者认为,有关MMP8 的新发现将促使对这一群基因的其它基因进行研究。他们写道,这些发现强调需要检测每个 MMP基因的个别角色,以精准定义它在癌症上的功能。
  
  Samuels博士解释,后续研究需特别注意,MMP8研究发现并无法直接导向黑色素瘤的新药。她向Medscape Oncology表示,不幸的是,我们无法就此基因发展一个抑制剂。反之,此研究发现证明一群基因类混有肿瘤抑制基因与致癌基因。
  
  Samuels博士指出,底线是,我们不应假定一群基因是致癌基因或者肿瘤抑制基因,须对这组MMP基因的其它基因,包括突变的基因都进行研究之后,才可以研究个别化治疗。
  
  【突变分析获得发现】
  NIH试图以进行新研究确认MMP基因是否造成黑色素瘤的基因改变。他们有充分理由进行此研究。
  
  如前述,MMP基因与癌症转移有关。不过,在老鼠研究中,研究者认为MMP有一种抗肿瘤效果。他们写道,特别是在MMP8-不足之老鼠发现皮肤肿瘤发生率增加。有关MMP的矛盾信息(肿瘤生长剂与产生抗肿瘤效果),引起研究者对个别MMP在特定癌症之个别角色的深入分析。
  
  黑色素瘤是第一种被选上研究的癌症。作者表示,该研究首次对MMP基因群进行系统性突变分析。
  
  为了研究MMP基因,研究者使用共同作者、国家癌症研究中心外科主任Steven Rosenberg博士搜集的79名侵犯性黑色素瘤病患的肿瘤与血液样本。
  
  在比较了这些病患的一系列MMP肿瘤基因与正常DNA之后,研究者在黑色素肿瘤的23个基因中的8个MMP基因辨识出28种不同突变 。
  
  肿瘤样本中,这些突变的分布频率与类型不同。在分析的肿瘤中,23%有至少1个MMP 基因突变。尤其,超过6%的肿瘤在MMP8有突变,超过7%在MMP27有突变,这两个是样本中突变频率最高的基因。
  
  在后续体外与体内(老鼠)的MMP8实验中,研究者指出,野生型MMP8与抑制黑色素瘤细胞生长有关,突变型MMP8 则无关。
  
  例如,研究者发现,注射野生型MMP8的老鼠不会发生皮肤溃疡,这是黑色素瘤癌症侵犯性的重要测量指标。不过,注射突变MMP8的老鼠会发生溃疡与肺部转移。
  
  研究者总结表示,整并基因、生化与细胞资料显示,MMP8是人类黑色素瘤的一个肿瘤抑制因子。后续研究最终在希望根据特定肿瘤的MMP突变基础,研发个别化治疗 。
  
  国家老化研究中心以及国家人类基因组图研究中心资助本研究。研究者宣告没有相关财务关系。
  
  Nat Genet. 于印刷前在线发表于2009年3月29日。
  
  

Suppressor of Melanoma Tumor Growth Identified

By Nick Mulcahy
Medscape Medical News

April 3, 2009 — A gene that suppresses tumor growth in melanoma has been identified by researchers at the National Institutes of Health (NIH). The gene, known as matrix metalloproteinase-8 (MMP8), could pave the way for new individualized therapies for melanoma, write the authors of a new study that was published online March 29 in Nature Genetics.

The new finding also provides insight into why MMP inhibitors, once considered promising anticancer agents, disappointed clinically.

MMPs are enzymes that degrade components of cells, including the extracellular matrix, explain the study authors, led by Lavanya H. Palavalli, MD, from the National Human Genome Research Institute (NHGRI) at the NIH, in Bethesda, Maryland. The enzymes help the body break down and recycle proteins, and thus play a role in the process of remodeling skin after sunburns, cuts, or other injuries.

MMP8 is 1 of a family of 23 MMP genes. This family of genes has been associated with cancer metastasis, say the study authors.

MMP genes that mutate have been thought to be oncogenes, or promoters of cancer cell growth. Thus, the suppression of MMP activity with MMP inhibitors was the focus of oncologic research and drug development. There have been "decades of research on MMPs," note the authors, but it has proven fruitless. "Clinical trials using these inhibitors showed no effect and, occasionally, accelerated tumor growth," write the authors.

The new NIH research hints at why MMP inhibitors and MMP suppression were problematic and why MMP8 holds promise as a melanoma tumor suppressor.

Through a series of experiments, the NIH investigators discovered that the expression of wild-type, or normal, MMP8 — but not mutant MMP8 — in human melanoma cells inhibited those melanoma cells from growing. Thus, expression of some (the wild-type) MMP8 genes inhibit melanoma cell growth.

The finding is consistent with the molecular understanding of cancer, suggested 1 of the authors.

"We often talk about cancer as though it is 1 disease, and cancers do have many common denominators. But when we look at the DNA level, we see that different cancers have different genetic profiles, and so do different patients who have the same cancer," said the study's senior author, Yardena Samuels, PhD, in a statement. She is an investigator in the Cancer Genetics Branch of the NHGRI's Division of Intramural Research.

The new finding about MMP8 should spur research on the rest of this gene family, suggest the authors. "These findings emphasize the need to test the role of each MMP in an individual manner and to precisely define its functional role in cancer," they write.

The need for further research is partially related to the fact that the MMP8 finding will not directly lead to a new drug for melanoma, explained Dr. Samuels. "Unfortunately, this is not a gene that we can develop an inhibitor for," she told Medscape Oncology. Instead, the promise of the findings is they that prove that a family of genes can be a mix of tumor suppressors and oncogenes.

"The bottom line is, we shouldn assume that a gene family is oncogenes or tumor-suppressor genes," Dr. Samuels added, explaining that individualized therapies will potentially follow as the rest of the family of MMP genes, including mutations, is researched.

Mutational Analysis Yields the Finding

The NIH undertook their new study in an effort to determine whether MMP genes are genetically altered in melanoma. There was good reason for the investigation.

As mentioned above, MMPs had been associated with cancer metastasis. However, in mouse models, there was the suggestion that MMPs had an antitumor effect, note the authors. "In particular, an increase in skin-tumor incidence was seen in MMP8-deficient mice," they write. The conflicting information about MMPs (agents of tumor growth vs producers of an antitumor effect) called for "an indepth analysis of the specific role of individual MMPs in particular cancer types," observe the authors.

Melanomas were chosen as the first cancer type. The study is the first systematic mutational analysis of the MMP family, say the authors.

To study the MMP genes, the researchers used a bank of tumor and blood samples collected from 79 patients with aggressive melanoma by coauthor Steven Rosenberg, MD, PhD, chief of surgery at the National Cancer Institute.

After comparing the sequence of MMP genes in tumors and normal DNA from the same patients, the researchers identified 28 different mutations in 8 MMP genes (from a total of 23 genes) in the melanoma tumors.

These mutations were distributed in different frequencies and patterns among the tumor samples. Of the tumors analyzed, 23% had at least 1 MMP gene mutation. Notably, more than 6% of tumors had mutations in MMP8 and more than 7% had mutations in MMP27, making them the most frequently mutated genes in the samples.

In a series of subsequent in vitro and in vivo (mice) experiments that focused on MMP8, the researchers note that the expression of wild-type but not mutant MMP8 was associated with inhibition of melanoma cell growth.

For example, the researchers found that mice injected with cells expressing wild-type MMP8 did not develop skin ulcers, which are important measures of cancer aggressiveness in melanoma. However, mice injected with cells expressing mutated MMP8 developed ulcerations and metastases in their lungs.

A combination of genetic, biochemical, and cellular data suggests that MMP8 is a tumor suppressor in human melanoma, they summarize. Further research might eventually allow the "development of individualized therapy on the basis of the mutant MMP present in the specific tumors," the authors conclude.

This study was funded by the National Institute on Aging and the National Human Genome Research Institute. The researchers have disclosed no relevant financial relationships.

Nat Genet. Published online before print March 29, 2009.

    
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