Post-transplant Cutaneous Squamous Cell Carcinoma and Macrophage Migration Inhibitory Factor

移植后皮肤鳞状细胞癌与巨噬细胞迁移抑制因子

• 批准号: 9098268
• 负责人: TATIANA M OBERYSZYN
• 金额: $ 20.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098268
• 关键词: Acute; Adjuvant; Age; American; Annual Reports; Basal cell carcinoma; Biopsy; Carcinomatosis; Caring; Cells; Cessation of life; Chronic; Coin; Cutaneous; Development; Environment; Environmental Carcinogens; Excision; Frequencies; General Population; Guidelines; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immigration; Immune; Immunocompetent; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Inflammation; Inflammatory Response; Intervention; Islets of Langerhans Transplantation; Kidney Transplantation; Knockout Mice; Length; Lesion; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Migration Inhibitory Factor; Modeling; Mohs Surgery; Morbidity - disease rate; Mus; Neoplasm Metastasis; Organ; Organ Transplantation; Patients; Play; Population; Pre-Clinical Model; Premalignant; Preventive; Radiation; Reconstructive Surgical Procedures; Recurrence; Regimen; Risk; Role; Screening for Skin Cancer; Sentinel; Site; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Solid; Squamous cell carcinoma; Staging; Surgeon; Testing; The Sun; Therapeutic; Therapeutic Intervention; Therapeutic immunosuppression; Time; Topical application; Transplant Recipients; Transplantation; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; Wild Type Mouse; Woman; chemokine; chemotherapy; cytokine; graft function; immunosuppressed; inhibitor/antagonist; keratinocyte; lymph nodes; melanoma; men; model development; mortality; mouse model; novel; overexpression; phenylpyruvate tautomerase; pre-clinical; predictive modeling; prevent; public health relevance; screening; sex; skin squamous cell carcinoma; standard of care; treatment strategy; tumor

 DESCRIPTION (provided by applicant): Ultraviolet light B (UVB; 290-320 nm) is a major environmental carcinogen that has been implicated in the development of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively known as nonmelanoma skin cancers (NMSC). As highlighted by the recent Surgeon General's Call to Action, these skin tumors are the most common form of cancer in humans, with over 3.5 million new cases identified in the United States each year. It was recently estimated that between 3932 and 8791 individuals died from cutaneous SCC in the United States in 2012, just slightly fewer than deaths from melanoma. The mortality rate greatly increases in the immunosuppressed population such as solid organ transplant recipients (OTR). In these patients SCC is vastly over-represented compared with its frequency in non-immunosuppressed patients. Organ transplantation increases the risk of development of SCC by 65-200 fold. In fact the term "catastrophic cutaneous carcinomatosis" has been coined to describe the development of SCCs in these patients. Cases of catastrophic cutaneous carcinomatosis may require decreasing immunosuppressive therapy risking the loss of the transplanted organ. As seen in the immunocompetent population, sex plays a strong role, with immunosuppressed men having greater risk of developing SCC than women. Clearly more effective preventive and/or treatment strategies are needed to prevent the morbidity and mortality resulting from SCC development in these patients. Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that is overexpressed in several cancers including melanoma and head/neck SCC in humans. We have demonstrated in immune competent MIF KO and wild type mice treated with a pharmacological MIF inhibitor (MIFi) following chronic UVB exposure that this cytokine likewise contributes to the development of UVB- induced SCC of the skin. To date we are not aware of any studies examining the effects of immunosuppressive therapies on cutaneous levels of MIF. The studies in the current application will use this pre-clinical model to test the hypothesis that increases in UVB-induced SCC observed in OTR are mediated at least in part by elevated cutaneous MIF levels. Studies in Aim 1 will use the preclinical Skh-1 murine model to determine the efficacy of therapeutic intervention with a MIFi prior to the initiation of immunosuppressive therapy on UVB induced tumor development in the sexes. Studies in Aim 2 will determine the efficacy of MIFi treatment in inducing regression of established tumors in the sexes under an immunosuppressive environment. Completion of these studies will provide important information about a novel intervention/treatment strategy for catastrophic cutaneous carcinomatosis in OTR.

 描述（由适用提供）：紫外线B（UVB; 290-320 nm）是一种主要的环境致癌物，在碱性细胞癌（BCC）（BCC）和鳞状细胞癌（SCC）的发展中已实施，集体称为非黑素瘤皮肤癌（NMSC）。正如最近外科医生的行动呼吁所强调的那样，这些皮肤肿瘤是人类最常见的癌症形式，每年在美国发现超过350万例新病例。最近估计，2012年在美国，3932和8791个人死于皮肤SCC，略低于黑色素瘤死亡。免疫抑制人群（例如固体器官移植受者（OTR））的死亡率大大增加。在这些患者中，与非免疫抑制患者相比，SCC的频率大大过高。器官移植将SCC发展的风险增加65-200倍。实际上，“灾难性的皮肤癌”一词是为了描述这些患者的SCC的发展。灾难性的皮肤癌病例可能需要降低免疫抑制治疗，冒着移植器官丧失的风险。从免疫能力的人群中可以看出，性别起着强大的作用，免疫抑制的男性比女性具有更大的SCC的风险。显然，需要采取更有效的预防和/或治疗策略，以防止这些患者的SCC发育引起的发病率和死亡率。巨噬细胞迁移抑制因子（MIF）是一种免疫调节性细胞因子，在人类中包括黑色素瘤和头颈SCC在内的几种癌症中过表达。我们在慢性UVB暴露后用药物MIF抑制剂（MIFI）治疗的免疫能力MIF KO和野生型小鼠证明了这种细胞因子同样有助于发育UVB诱导的SCC皮肤。迄今为止，我们尚未意识到有任何研究检查免疫抑制疗法对皮肤MIF水平的影响。当前应用中的研究将使用此临床前模型来检验以下假设。 在OTR中观察到的UVB诱导的SCC的增加至少部分是通过皮肤MIF水平升高的。 AIM 1中的研究将使用临床前SKH-1鼠模型来确定在对UVB诱导性别诱导性肿瘤发育的免疫抑制治疗之前，先用MIFI使用MIFI进行治疗性干预的有效性。 AIM 2中的研究将确定MIFI治疗在免疫抑制环境下诱导性别肿瘤的诱导消退的有效性。这些研究的完成将提供有关OTR中灾难性皮肤癌的新型干预/治疗策略的重要信息。