Erin Nuray, Zhao Wei, Bylander John, Chase Gary, Clawson Gary
Department of Pathology, Gittlen Cancer Research Foundation, Hershey Medical Center, H059, Pennsylvania State University, 500 University drive, Hershey, PA 17033, USA.
Breast Cancer Res Treat. 2006 Oct;99(3):351-64. doi: 10.1007/s10549-006-9219-7. Epub 2006 Apr 1.
Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.
据报道，辣椒素诱导感觉神经元失活可增强小鼠乳腺癌细胞系的转移，特别是增强心肌转移。在此，我们对辣椒素处理的小鼠与对照小鼠原发肿瘤中基因表达模式的变化进行了表征。我们鉴定出一小群基因（17个），其表达水平均显著下降。所有鉴定出的基因都与细胞生长、分化和/或癌症进展有关。对三个代表性基因进行了进一步研究，它们分别是半胱天冬酶-7（一种凋亡执行蛋白）、ADAM-10（一种解整合素和金属蛋白酶）和Elk-3（Ets因子三元因子亚家族的转录抑制因子）。与对照（载体处理）动物相比，辣椒素处理动物原发肿瘤中这三种基因在蛋白水平均显著下调，并且在细胞培养中它们的表达也消失了。在培养的细胞系中，Elk-3和半胱天冬酶-7在体外不表达，这表明它们的表达是由肿瘤微环境诱导的。半胱天冬酶-7表达缺失预计会导致凋亡途径功能丧失。乍一看，ADAM-10表达缺失预计会因基质金属蛋白酶活性丧失而导致侵袭能力下降。然而，事实似乎恰恰相反。我们发现ADAM-10实际上可水解P物质。具体而言，ADAM-10从P物质产生与中性内肽酶相同的生长抑制产物（即SP(1-7)），因此ADAM-10表达缺失实际上导致P物质生长抑制肽产生减少。同样，ADAM-10也能有效水解降钙素基因相关肽，它可能与P物质协同作用。最后，Ets转录抑制功能的过度活跃与肿瘤发生抑制有关（例如Erf和Mef），此外，Elk-3表达缺失也可能因其假定的抗炎活性丧失而与肿瘤发生有关。文献中有轶事证据表明，其余下调基因可能也有助于该乳腺癌模型中更具侵袭性表型的发展。
