Wnt signaling in senescence, nevogenesis and melanomagenesis

2010年，美国约有68,000例黑色素瘤新病例，约8,700人死于这种疾病（www.cancer.org）。在英国，黑色素瘤的发病率在过去25年里比其他任何癌症的发病率都要高（http://www.cancerhelp.org.uk/）。尽管靶向黑色素瘤治疗最近取得了进展（例如vemurafenib），但晚期黑色素瘤的预后仍然令人沮丧。新一代的靶向治疗提供了显著但适度的延长生存期。然而，耐药性和疾病进展总是会发生。因此，迫切需要找到更好的方法来防治这种疾病，也许重点放在更早的风险评估和化学预防上。黑色素瘤是由皮肤、头发和眼睛中的黑色素细胞转化和不受控制的生长引起的。最早的黑色素细胞肿瘤是正常的良性痣（痣），是由皮肤中表达癌基因的黑色素细胞克隆增殖扩增引起的。尽管绝大多数良性人类痣不会发展为黑色素瘤，但大约25%的黑色素瘤被认为是由原有的痣引起的。了解痣到黑色素瘤的发展过程对了解黑色素瘤的起源至关重要。大多数痣被认为是通过一种叫做细胞衰老的过程来防止发展成黑色素瘤的，这是一种不可逆的增殖抑制，可以阻止潜在癌细胞的增殖。在这个应用中，我们将更好地定义痣黑素细胞的分子状态。通过这样做，我们将告知黑色素瘤的起源，是否来自痣或非痣黑色素细胞。这一应用可以为黑色素瘤风险评估和黑色素瘤化学预防策略提供生物标志物。例如，一种减少晚年黑色素瘤发病率的微创方法可能是局部局部应用特定抑制剂来抑制儿童和青少年的痣形成，这是大多数获得性痣形成的时期。

In 2010 in the US, there were approximately 68,000 new cases of melanoma and about 8,700 deaths from this disease (www.cancer.org). In the UK, the incidence of melanoma has increased more than any other cancer in the last 25 years (http://www.cancerhelp.org.uk/). Despite recent advances in targeted melanoma therapies (for example, vemurafenib) the prognosis for advanced melanoma remains dismal. The new generation of targeted therapies provide a significant, but modest, prolonged survival. However, drug resistance and disease progression invariably occurs. Consequently, there is an urgent need for better ways to combat this disease, perhaps focused on much earlier risk assessment and chemoprevention. Melanoma results from transformation and uncontrolled growth of melanocytes, pigment producing cells in the skin, hair and eyes. The earliest apparent melanocytic neoplasms are normal benign nevi (moles), which result from clonal proliferative expansion of oncogene-expressing melanocytes in the skin. Although the vast majority of benign human nevi do not progress to melanoma, approximately 25% of melanoma are thought to result from a pre-existing nevus. Understanding the progression of nevi to melanoma is critical to understanding the origins of melanoma. Most nevi are thought to be prevented from progression to melanoma by a process called cellular senescence - an irreversible proliferation arrest that prevents proliferation of potentially cancerous cells. In this application, we will better define the molecular status of nevus melanocytes. By doing so, we will inform on the origins of melanoma, whether from nevus or non-nevus melanocytes. This application can lead to biomarkers for melanoma risk assessment in nevi and strategies for melanoma chemoprevention. For example, one minimally invasive approach to reduce incidence of melanoma in later life might be local topical application of specific inhibitors to developing nevi in childhood and adolescence, when most acquired nevi form.