一個國際性的科學家團隊鑒定出一種與黑色素瘤轉移有關的重要分子,。通過引入一種模仿這個鏈接而制造的合成性縮胺酸，研究人員得以抑制這個細胞間的交互作用,，并且阻止癌細胞從原始的發(fā)生位置轉移到其它部位。
抑制這種蛋白質聯結也可以抑制血管新生作用,，并且加速細胞死亡或凋亡,。這篇研究結果發(fā)表于7月號的Cancer Research，新提出的治療將可以防止或限制皮膚癌轉移,。這些合成性縮胺酸可以減少腫瘤細胞轉移及血管新生并增加細胞壞死,，這對于皮膚癌治療的發(fā)展是相當重大的進展。
如研究中所描述,，黑色素細胞瘤的癌細胞傳播需要二種蛋白質之間的交互作用,，其中一個是位于細胞表面的CD44，和細胞外基質蛋白質laminin α5,。CD44被認為是proteogylcan,，一種含有碳水化合物的蛋白質長鏈，自它的蛋白質核心向外延伸,，使它的結構類似于瓶刷,。碳水化合物的邊鏈稱為glycosaminoglycans(GAGs)，可與其它細胞壁膜外的分子產生交互作用,。
CD44則是由細胞制造而安置在細胞表面膜上,，在癌細胞中經常會過度表現。Laminin α5分子是胞外基質蛋白質,，占據細胞之間的空間,，并且提供器官和組織的定義和結構鑒定,。
研究小組測試了113種合成的縮胺酸,，其中縮胺酸A5G27可與laminin α5競爭CD44的受體。因此可以阻斷這種蛋白質之間的交互作用,，研究結果發(fā)現癌細胞變小,，且腫瘤中無新生的血管。
Scientists Identify Molecular Link Driving Spread of Skin Cancer
Finding holds promise for inhibition of metastasis with targeted, synthetic peptides
PHILADELPHIA – An international team of scientists has identified an important molecular link involved in the spread – or metastasis – of melanoma to other organs such as the lungs.
By introducing a synthetic peptide that mimics one component of this link, the researchers blocked this cellular interaction, significantly deterring the migration of cancer cells beyond the original tumor site. Blocking this protein linkage also was shown to inhibit angiogenesis—the creation of blood vessels that nourish new, secondary tumors—and spur cell death or apoptosis.
The results, published in the July 15 issue of the journal Cancer Research, open the door to the prospect of targeted therapeutics capable of preventing or limiting the metastasis of skin cancer.
“The ability of these synthetic peptides to reduce tumor cell metastasis and angiogenesis and increase apoptosis may be important in the development of therapeutics for malignancy,” said Hynda Kleinman, Ph.D., chief, cell biology section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md.
As described in their study, the spread of melanoma cancer cells requires the interaction of two proteins, one located on the cell’s surface called CD44, and an extracellular matrix protein known as laminin α5.
CD44 is considered a proteogylcan, which is a protein that has lengthy chains of carbohydrates that extend outward from its protein core, giving it a structure similar to a bottle brush. Carbohydrate side chains, called glycosaminoglycans (GAGs), can interact with other molecules outside of the cell wall membrane. CD44 is produced by cells and positioned on their cell surface membrane. It is often overexpressed in cancer cells. Dr. Kleinman and her associates determined that the GAG near one end of the CD44 protein backbone binds to a specific sequence of amino acid residues in laminin α5.
The laminin α5 molecule is an extracellular matrix protein that occupies areas between cells in the body and gives definition and structural identity to organs and tissue.
The research team, which includes scientists from Tokyo Metropolitan Komagome Hospital and Hokkaido University in Japan, tested a library of 113 synthetic peptides for their ability to attach to melanoma cells and for their effect on the colonization of melanoma cells in the lung. Those peptides were constructed to match sequences along the laminin α5 globular domain. The scientists observed that the peptide A5G27 competed with laminin α5 in binding to the CD44 receptor at the site of the specific CD44 GAG side chain. A5G27 consists of 13 amino acid residues that are consistent with the laminin α5 sequence extending between residues 2893 and 2904.
Kleinman’s colleagues documented the ability of A5G27 to inhibit metastasis of skin cancer cells to the lungs of mice. Furthermore, when melanoma cells were placed under the skin of mice treated with A5G27 synthetic peptides, the cells formed a tumor that was smaller in size and lacking in ample growth of novel blood vessels, compared to the tumors that developed in mice that received no synthetic peptide treatment.
By identifying the peptide that inhibits the laminin α5–CD44 interaction from propelling cancer cell migration, invasion and angiogenesis, the research team uncovered a potentially key target for molecular therapy.
More than one million cases of basal cell or squamous cell skin cancers occur annually; melanoma and other non-epithelial skin cancers will cause an estimated 10,250 deaths in 2004.
