Melanoma Metabolism: Cell Survival and Resistance to Therapy.
- 作者列表："Luís R","Brito C","Pojo M
:Cutaneous melanoma is one of the most aggressive types of cancer, presenting the highest potential to form metastases, both locally and distally, which are associated with high death rates of melanoma patients. A high somatic mutation burden is characteristic of these tumours, with most common oncogenic mutations occurring in the BRAF, NRAS and NF1 genes. These intrinsic oncogenic pathways contribute to the metabolic switch between glycolysis and oxidative phosphorylation metabolisms of melanoma, facilitating tumour progression and resulting in a high plasticity and adaptability to unfavourable conditions. Moreover, melanoma microenvironment can influence its own metabolism and reprogram several immune cell subset functions, enabling melanoma to evade the immune system. The knowledge of the biology, molecular alterations and microenvironment of melanoma has led to the development of new targeted therapies and the improvement of patient care. In this work, we reviewed the impact of melanoma metabolism in the resistance to BRAF and MEK inhibitors and immunotherapies, emphasizing the requirement to evaluate metabolic alterations upon development of novel therapeutic approaches. Here we summarized the current understanding of the impact of metabolic processes in melanomagenesis, metastasis and microenvironment, as well as the involvement of metabolic pathways in the immune modulation and resistance to targeted and immunocheckpoint therapies.
: 皮肤黑色素瘤是最具侵袭性的癌症类型之一，在局部和远端形成转移的可能性最高，与黑色素瘤患者的高死亡率相关。高体细胞突变负荷是这些肿瘤的特征，最常见的致癌突变发生在BRAF、NRAS和NF1 基因中。这些内在的致癌途径有助于黑色素瘤糖酵解和氧化磷酸化代谢之间的代谢转换，促进肿瘤进展，导致高度可塑性和对不利条件的适应性。而且，黑色素瘤微环境可以影响自身代谢，重新编程几个免疫细胞亚群功能，使黑色素瘤能够逃避免疫系统。黑色素瘤的生物学、分子改变和微环境的知识导致了新的靶向治疗的发展和患者护理的改善。在这项工作中，我们综述了黑色素瘤代谢在BRAF和MEK抑制剂和免疫疗法抵抗中的影响，强调了开发新的治疗方法时评估代谢改变的要求。在此，我们总结了目前对代谢过程在黑斑病发生、转移和微环境中的影响的理解，以及代谢途径在免疫调节和对靶向和免疫检查点治疗的抵抗中的参与。
METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.
METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.