Martinez-Font Esther, Pérez-Capó Marina, Vögler Oliver, Martín-Broto Javier, Alemany Regina, Obrador-Hevia Antònia
Group of Advanced Therapies and Biomarkers in Clinical Oncology, Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, 07122 Palma, Spain.
Health Research Institute of the Balearic Islands (IdISBa), 07010 Palma, Spain.
Cancers (Basel). 2021 Nov 3;13(21):5521. doi: 10.3390/cancers13215521.
Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed.
软组织肉瘤（STS）是一组非常异质性的罕见肿瘤，由50多种源自间充质组织的不同组织学亚型组成。尽管它们具有异质性，但基于阿霉素（DXR）的化疗已经使用了40年，并且仍然是局部晚期不可切除或转移性STS的标准一线治疗方法，尽管与其他化疗药物联合使用并不能提高总体生存率。从这个意义上说，开发新的治疗方法仍然是一个很大程度上未实现的目标。WNT/β-连环蛋白信号通路参与胚胎发育的各种基本过程，包括间充质干细胞的增殖和分化。尽管该通路的作用在上皮源性肿瘤中已得到广泛研究，但对其在间充质肿瘤中的相关性知之甚少。本综述涵盖了STS中WNT信号通路最重要的分子改变。检测这些改变并了解它们对控制肉瘤发生发展和进展的那些通路的功能后果，对于拓宽当前关于STS的知识以及识别新的药物靶点至关重要。在这方面，还讨论了目前调节WNT信号的治疗选择和候选药物，这些药物通常根据它们在β-连环蛋白上游或下游的相互作用位点进行分类，以及它们对STS可能的临床影响。
