確認黑色素瘤抑制劑

作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　April 3, 2009 — 國家健康研究中心(NIH)的研究者確認了一種可以抑制黑色素瘤的基因。線上發表於3月29日Nature Genetics期刊的一篇研究寫道，此基因稱為「基質金屬蛋白酵素-8(MMP8)」，可供作為黑色素瘤的新個人化治療。
　　
　　這項新發現也讓人可以理解，曾被視為有效的抗癌製劑、MMP抑制劑，為什麼在臨床上是令人失望的。
　　
　　國家人類基因組圖研究中心(NHGRI)的Lavanya H. Palavalli醫師領導的研究者解釋，MMP是降解細胞成分的酵素，包括細胞外基質。這些酵素幫助身體蛋白質分解與再度循環，因此在曬傷、切割傷或其他傷害後的皮膚重組過程扮演重要角色。
　　
　　MMP8是23種MMP基因之一。研究者表示，已知這一群基因與癌症轉移有關。
　　
　　MMP基因突變被視為致癌基因，或者促進癌細胞生長。因此，使用MMP抑制劑抑制MMP活性是腫瘤研究與藥物研發的焦點。研究者指出，對MMP的研究已有數十年，但它已經證明是不成功的。作者寫道，使用這些抑制劑的臨床試驗顯示沒有效果，且偶爾會加速腫瘤生長。
　　
　　新的NIH研究暗示何以MMP抑制劑與MMP抑制有問題，何以MMP8 對黑色素瘤抑制有用。
　　
　　透過一系列的實驗，NIH研究者發現，人類黑色素腫瘤細胞是野生型的、正常的MMP8 — 也就是沒有突變的MMP8，可以抑制那些黑色素瘤細胞生長。因此，抑制某些(野生型)MMP8 基因可抑制黑色素瘤細胞生長。
　　
　　作者之一認為，此發現與對癌症分子的理解一致。
　　
　　資深研究作者Yardena Samuels博士在聲明中表示，我們通常將癌症視為一種疾病，癌症也確實有很多共同起源。但是當我們就DNA觀點討論時，發現不同的癌症有不同的基因資料，所以不同的病患會有同樣的癌症。她是NHGRI內部研究小組癌症基因組的研究員。
　　
　　研究者認為，有關MMP8 的新發現將促使對這一群基因的其他基因進行研究。他們寫道，這些發現強調需要檢測每個 MMP基因的個別角色，以精準定義它在癌症上的功能。
　　
　　Samuels博士解釋，後續研究需特別注意，MMP8研究發現並無法直接導向黑色素瘤的新藥。她向Medscape Oncology表示，不幸的是，我們無法就此基因發展一個抑制劑。反之，此研究發現證明一群基因類混有腫瘤抑制基因與致癌基因。
　　
　　Samuels博士指出，底線是，我們不應假定一群基因是致癌基因或者腫瘤抑制基因，須對這組MMP基因的其他基因，包括突變的基因都進行研究之後，才可以研究個別化治療。
　　
　　【突變分析獲得發現】
　　NIH試圖以進行新研究確認MMP基因是否造成黑色素瘤的基因改變。他們有充分理由進行此研究。
　　
　　如前述，MMP基因與癌症轉移有關。不過，在老鼠研究中，研究者認為MMP有一種抗腫瘤效果。他們寫道，特別是在MMP8-不足之老鼠發現皮膚腫瘤發生率增加。有關MMP的矛盾資訊(腫瘤生長劑與產生抗腫瘤效果)，引起研究者對個別MMP在特定癌症之個別角色的深入分析。
　　
　　黑色素瘤是第一種被選上研究的癌症。作者表示，該研究首次對MMP基因群進行系統性突變分析。
　　
　　為了研究MMP基因，研究者使用共同作者、國家癌症研究中心外科主任Steven Rosenberg博士蒐集的79名侵犯性黑色素瘤病患的腫瘤與血液樣本。
　　
　　在比較了這些病患的一系列MMP腫瘤基因與正常DNA之後，研究者在黑色素腫瘤的23個基因中的8個MMP基因辨識出28種不同突變 。
　　
　　腫瘤樣本中，這些突變的分布頻率與類型不同。在分析的腫瘤中，23%有至少1個MMP 基因突變。尤其，超過6%的腫瘤在MMP8有突變，超過7%在MMP27有突變，這兩個是樣本中突變頻率最高的基因。
　　
　　在後續體外與體內(老鼠)的MMP8實驗中，研究者指出，野生型MMP8與抑制黑色素瘤細胞生長有關，突變型MMP8 則無關。
　　
　　例如，研究者發現，注射野生型MMP8的老鼠不會發生皮膚潰瘍，這是黑色素瘤癌症侵犯性的重要測量指標。不過，注射突變MMP8的老鼠會發生潰瘍與肺部轉移。
　　
　　研究者總結表示，整併基因、生化與細胞資料顯示，MMP8是人類黑色素瘤的一個腫瘤抑制因子。後續研究最終在希望根據特定腫瘤的MMP突變基礎，研發個別化治療 。
　　
　　國家老化研究中心以及國家人類基因組圖研究中心資助本研究。研究者宣告沒有相關財務關係。
　　
　　Nat Genet. 於印刷前線上發表於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.