Molecular Pathogenesis of Sporadic Desmoid Tumours and Its Implications for Novel Therapies: A Systematised Narrative Review

Abstract

Sporadic desmoid-type fibromatosis is a rare, fibroblastic soft-tissue neoplasm with local aggressiveness but no metastatic potential. Aberrant Wnt/β-catenin signalling has been extensively linked to desmoid pathogenesis, although little is known about other molecular drivers and no established treatment approach exists. We aimed to summarise the current literature regarding the molecular pathogenesis of sporadic desmoid-type fibromatosis and to discuss the effects of both current and emerging novel therapies targeting these mechanisms. A literature search was conducted of MEDLINE^® ALL and EMBASE databases for published studies (2000-August 2021) using keywords related to 'fibromatosis aggressive', 'immunohistochemistry', 'polymerase chain reaction' and 'mutation'. Articles were included if they examined the role of proteins in sporadic or extra-abdominal human desmoid-type fibromatosis pathogenesis. Searching identified 1684 articles. Following duplicate removal and eligibility screening, 36 were identified. After a full-text screen, 22 were included in the final review. At least 47% of desmoid-type fibromatosis cases displayed aberrant β-catenin immunoreactivity amongst ten studies. Cyclin D1 overexpression occurred in at least 40% of cases across five studies. Six studies reported oestrogen receptor-β expression with a range of 7.4-90%. Three studies implicated matrix metalloproteinases, with one study demonstrating vascular endothelial growth factor overexpression. One study explored the positive relationship between cyclooxygenase-2 and platelet-derived growth factor receptor-β. Aberrant Wnt/β-catenin signalling is a well-established pathogenic driver that may be targeted via downstream modulation. Growth factor signalling is best appreciated through the clinical trial effects of multi-targeted tyrosine kinase inhibitors, whilst oestrogen receptor expression data may only offer a superficial insight into oestrogen signalling. Finally, the tumour microenvironment presents multiple potential novel therapeutic targets.

Fig. 1

Wnt/β-catenin signalling pathway. The Wnt/β-catenin pathway coordinates cell proliferation, differentiation and fate during both embryogenesis and in normal adult tissues. a In the absence of a Wnt signal, cytoplasmic β-catenin that is not involved in cell-cell adhesion interacts with a degradation complex comprising axin, APC, GSK3 and CK1. Here, the sequential phosphorylation of β-catenin by CK1 and GSK3 marks it for ubiquitylation and degradation. This constant degradation prevents β-catenin from entering the nucleus and promoting the transcription of Wnt target genes. b The binding of Wnt to its frizzled receptor and LRP co-receptor leads to the recruitment of dishevelled. Together, this complex recruits the degradation complex to the cell membrane where LRP becomes phosphorylated by GSK3 then CK1. Axin then binds to the phosphorylated LRP, resulting in the disassembly of the degradation complex. Consequently, the stabilisation of β-catenin allows it to accumulate and translocate into the nucleus. Here, it binds to the TCF/LEF promotor region to stimulate the transcription of Wnt target genes including CCND1 (cyclin D1), MYC, PTGS2 (cyclooxygenase-2), MMP7, VEGF and WISP1. With deregulated, constitutive activation, the resultant protein products may drive tumourigenesis by enhancing proliferation, angiogenesis and invasiveness [–14]. Created with BioRender.com

Fig. 2

Exclusion algorithm for retrieved articles using sporadic status and tumour location. E-AD extra-abdominal

Fig. 3

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) search strategy flow diagram. FAP familial adenomatous polyposis

Fig. 4

Joanna Briggs Institute critical appraisal for case-series via ROBINS-I [54]

Fig. 5

Key molecular drivers associated with desmoid tumour pathophysiology. a β-Catenin primarily coordinates cell proliferation, differentiation and fate, with its deregulated signalling being intrinsically linked to the development of several human cancers, such as skin, colon and breast cancer [13, 14]. Cyclin D1 and c-Myc signalling is commonly deregulated in tumourigenesis due to their promotional effects on cell proliferation by enhancing the G1 to S-phase transition of the cell cycle [34, 35]. b Cyclooxygenase-2 (COX2) is an inducible member of the cyclooxygenase family involved in multiple physiological purposes. In colorectal cancer, COX2 has been extensively implicated in promoting angiogenesis, invasion and proliferation through the upregulation of growth factors such as platelet-derived growth factor [37, 38]. The multi-functional transforming growth factor-beta (TGFβ) superfamily and related growth factors play complex and often opposing roles in cell proliferation, differentiation, regeneration and morphogenesis [41]. c Oestrogens are steroid hormones that promote growth, differentiation and reproduction throughout a range of human tissues. Their role in tumourigenesis has been extensively studied in breast cancer, where aberrant signalling drives proliferation, invasion and metastasis [44]. d Matrix metalloproteinases (MMPs) and related proteases play a pivotal role in cancer pathogenesis through their modulation of extracellular matrix, angiogenesis, cell migration and growth [48]. Vascular endothelial growth factor (VEGF) is a prominent angiogenic mediator whose expression is commonly upregulated in cancer tissue by various oncogenes, growth factors and hypoxia to sustain growth and invasion [52]. e The tumour suppressor genes RB1, CDKN2A and TP53 inhibit cell proliferation by arresting cells in the G1 phase of the cell cycle, with the latter protein being upregulated in response to DNA damage [53, 55]. f In its cell membrane function, β-catenin complexes with other proteins, such as α-catenin and N-cadherin, to mediate epithelial cell-cell adhesion and stability [57]. Created with BioRender.com. PDGFR platelet-derived growth factor receptor

Fig. 6

Aberrant Wnt/β-catenin signalling with mutated CTNNB1. T41A and S45F represent the two most common substitution mutations harboured by sporadic desmoid-type fibromatosis. These amino acid substitutions prevent β-catenin’s phosphorylation by GSK3 and CK1. Consequently, the mutated β-catenin is not marked for degradation, allowing it to accumulate and translocate into the nucleus where it promotes the unregulated transcription of specific target genes. The resultant protein products drive tumourigenesis by enhancing proliferation, angiogenesis and invasiveness [15, 58]. Created with BioRender.com. COX2 cyclooxygenase-2, MMP matrix metalloproteinase, S45F serine to phenylalanine substitution in codon 45, T41A threonine to alanine substitution in codon 41, VEGF vascular endothelial growth factor, WISP1 Wnt inducible signalling pathway protein 1