一个国际性的科学家团队鉴定出一种与黑色素瘤转移有关的重要分子。通过引入一种模仿这个链接而制造的合成性缩胺酸，研究人员得以抑制这个细胞间的交互作用，并且阻止癌细胞从原始的发生位置转移到其它部位。
抑制这种蛋白质联结也可以抑制血管新生作用，并且加速细胞死亡或凋亡。这篇研究结果发表于7月号的Cancer Research，新提出的治疗将可以防止或限制皮肤癌转移。这些合成性缩胺酸可以减少肿瘤细胞转移及血管新生并增加细胞坏死，这对于皮肤癌治疗的发展是相当重大的进展。
如研究中所描述，黑色素细胞瘤的癌细胞传播需要二种蛋白质之间的交互作用，其中一个是位于细胞表面的CD44，和细胞外基质蛋白质laminin α5。CD44被认为是proteogylcan，一种含有碳水化合物的蛋白质长链，自它的蛋白质核心向外延伸，使它的结构类似于瓶刷。碳水化合物的边链称为glycosaminoglycans(GAGs)，可与其它细胞壁膜外的分子产生交互作用。
CD44则是由细胞制造而安置在细胞表面膜上，在癌细胞中经常会过度表现。Laminin α5分子是胞外基质蛋白质，占据细胞之间的空间，并且提供器官和组织的定义和结构鉴定。
研究小组测试了113种合成的缩胺酸，其中缩胺酸A5G27可与laminin α5竞争CD44的受体。因此可以阻断这种蛋白质之间的交互作用，研究结果发现癌细胞变小，且肿瘤中无新生的血管。
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.
