TY - JOUR
T1 - Aberrant non-canonical WNT pathway as key-driver of high-grade serous ovarian cancer development
AU - Zannoni, Gian Franco
AU - Angelico, Giuseppe
AU - Santoro, Angela
PY - 2020
Y1 - 2020
N2 - Epithelial ovarian cancer (EOC), the deadliest among gynecologic malignancies, is ranked as the fifth leading cause of cancer deaths in females [1]. Based on morphological findings, cellular origins, clinical characteristics, and several molecular genetic/epigenetic alterations, EOC has been subdivided into five main types: high-grade serous (HGSC, 70%), endometrioid (EC, 10%), clear cell (CC, 10%), mucinous (MC, 3%), and low-grade serous carcinomas (LGSC, < 5%) that account for over 95% of cases [2]. HGSCs generally harbor TP53 alterations, a pronounced genomic instability and, also, inherited and somatic BRCA1 and BRCA2 mutations. The other abovementioned cancer types are frequently characterized by mutations in KRAS, BRAF, PTEN, and CTNNB1 (Beta-catenin), and a relatively stable karyotype [2].
In this complex and heterogeneous scenario, the Wnt/beta-catenin signaling pathway, known to regulate stemness, cellular homeostasis, embryonic development, and physiological processes, in a broad spectrum of stem cell niches (also including the ovarian site), seems to play an important role in ovarian cancer [3].
WNT proteins are a large family of secreted glycoproteins activating at least three signaling pathways: the canonical pathway (WNT-beta-catenin), the non-canonical pathway (planar cell polarity), and WNT-Ca2+ pathway [4]. The first operates by stabilizing beta-catenin and translates a WNT signal into the transient transcription of a TCF/LEF target gene program; the second is beta-catenin independent and controls cell movement during morphogenesis [5]. Several WNT-antagonists, distinct in two types, are well known: (a) those ones binding to low-density lipoprotein receptor-related proteins (LRP-5 or LRP-6), including Sclerostin and Dickkopf (DKK) proteins, and (b) those ones interacting directly with WNT proteins, including WIF-1, Cerberus, and secreted Frizzled-related proteins (SFRPs) [6].
Different molecular events may determine the chronic activation of WNT target gene program in human cancers: (a) mutations in APC or Axin1 genes resulting in the production of truncated scaffold proteins being unable to bind beta-catenin [6]; (b) mutation of the conserved Ser/Thr phosphorylation sites at the N-terminus of beta-catenin [7, 8]; and (c) loss of WNT inhibitors through epigenetic silencing [6].
Although dysregulation of the WNT pathway via beta-catenin is a frequent event in several human cancers [7], its potential implications in ovarian cancer are still under investigation.
In particular, 16–54% of endometrioid and mucinous histotypes are characterized by mutations of beta-catenin or, with a considerably less frequency, APC, AXIN1, and AXIN2 [3].
However, the altered expression of beta-catenin (overexpression or alterations in subcellular location: nuclear/cytoplasmatic vs membrane) has been observed also in other histotypes (HGSC), where mutations in Wnt-related genes are relatively uncommon.
This suggests that the constitutive deregulation of Wnt signaling with the consequent over-activity of normal structured beta-catenin protein may contribute to cancer progression in ovarian HGSCs.
Evidence accumulated in the years supports Wnt pathway key role in EOC development, by promoting CSC (cancer stem cell) self-renewal, EMT (epithelial-mesenchimal transition), metastasis, and tumor angiogenesis, and suppressing tumor immunity/immune escape [8]. Data are limited regarding its potential role in predicting chemoresponse or its prognostic relevance [8].
Molecularly, different mechanisms could be involved in Wnt pathway hyperactivation: overexpression of ligands and receptors, under-expression of inhibitors of the Wnt/beta-catenin pathway, and altered expression of proteins that regulate beta-catenin/E-cadherin or beta-catenin/TCF interactions. In addition, the role of many non-coding RNAs (lncRNAs, miRNAs, and circRNAs) in modulating beta-catenin signa
AB - Epithelial ovarian cancer (EOC), the deadliest among gynecologic malignancies, is ranked as the fifth leading cause of cancer deaths in females [1]. Based on morphological findings, cellular origins, clinical characteristics, and several molecular genetic/epigenetic alterations, EOC has been subdivided into five main types: high-grade serous (HGSC, 70%), endometrioid (EC, 10%), clear cell (CC, 10%), mucinous (MC, 3%), and low-grade serous carcinomas (LGSC, < 5%) that account for over 95% of cases [2]. HGSCs generally harbor TP53 alterations, a pronounced genomic instability and, also, inherited and somatic BRCA1 and BRCA2 mutations. The other abovementioned cancer types are frequently characterized by mutations in KRAS, BRAF, PTEN, and CTNNB1 (Beta-catenin), and a relatively stable karyotype [2].
In this complex and heterogeneous scenario, the Wnt/beta-catenin signaling pathway, known to regulate stemness, cellular homeostasis, embryonic development, and physiological processes, in a broad spectrum of stem cell niches (also including the ovarian site), seems to play an important role in ovarian cancer [3].
WNT proteins are a large family of secreted glycoproteins activating at least three signaling pathways: the canonical pathway (WNT-beta-catenin), the non-canonical pathway (planar cell polarity), and WNT-Ca2+ pathway [4]. The first operates by stabilizing beta-catenin and translates a WNT signal into the transient transcription of a TCF/LEF target gene program; the second is beta-catenin independent and controls cell movement during morphogenesis [5]. Several WNT-antagonists, distinct in two types, are well known: (a) those ones binding to low-density lipoprotein receptor-related proteins (LRP-5 or LRP-6), including Sclerostin and Dickkopf (DKK) proteins, and (b) those ones interacting directly with WNT proteins, including WIF-1, Cerberus, and secreted Frizzled-related proteins (SFRPs) [6].
Different molecular events may determine the chronic activation of WNT target gene program in human cancers: (a) mutations in APC or Axin1 genes resulting in the production of truncated scaffold proteins being unable to bind beta-catenin [6]; (b) mutation of the conserved Ser/Thr phosphorylation sites at the N-terminus of beta-catenin [7, 8]; and (c) loss of WNT inhibitors through epigenetic silencing [6].
Although dysregulation of the WNT pathway via beta-catenin is a frequent event in several human cancers [7], its potential implications in ovarian cancer are still under investigation.
In particular, 16–54% of endometrioid and mucinous histotypes are characterized by mutations of beta-catenin or, with a considerably less frequency, APC, AXIN1, and AXIN2 [3].
However, the altered expression of beta-catenin (overexpression or alterations in subcellular location: nuclear/cytoplasmatic vs membrane) has been observed also in other histotypes (HGSC), where mutations in Wnt-related genes are relatively uncommon.
This suggests that the constitutive deregulation of Wnt signaling with the consequent over-activity of normal structured beta-catenin protein may contribute to cancer progression in ovarian HGSCs.
Evidence accumulated in the years supports Wnt pathway key role in EOC development, by promoting CSC (cancer stem cell) self-renewal, EMT (epithelial-mesenchimal transition), metastasis, and tumor angiogenesis, and suppressing tumor immunity/immune escape [8]. Data are limited regarding its potential role in predicting chemoresponse or its prognostic relevance [8].
Molecularly, different mechanisms could be involved in Wnt pathway hyperactivation: overexpression of ligands and receptors, under-expression of inhibitors of the Wnt/beta-catenin pathway, and altered expression of proteins that regulate beta-catenin/E-cadherin or beta-catenin/TCF interactions. In addition, the role of many non-coding RNAs (lncRNAs, miRNAs, and circRNAs) in modulating beta-catenin signa
KW - biosafety guidelines
KW - coronavirus
KW - cytology
KW - fine-needle aspiration
KW - histology
KW - personalized medicine
KW - biosafety guidelines
KW - coronavirus
KW - cytology
KW - fine-needle aspiration
KW - histology
KW - personalized medicine
UR - http://hdl.handle.net/10807/150765
U2 - 10.1007/s00428-020-02760-5
DO - 10.1007/s00428-020-02760-5
M3 - Article
SN - 0945-6317
SP - 1
EP - 3
JO - Virchows Archiv
JF - Virchows Archiv
ER -