Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

Ploeg, Phyllis van der; Uittenboogaard, Aniek; Bosch, Steven L.; Diest, Paul J. van; Wesseling-Rozendaal, Yvonne; Stolpe, Anja van de; Lambrechts, Sandrina; Bekkers, Ruud L.M.; Piek, Jurgen M.J.

doi:10.1016/j.ygyno.2022.01.027

Cited by 6 publications

(6 citation statements)

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“…It has been found that neoplastic transformation of the fallopian tube epithelium into STIC and further disease progression are accompanied by abnormal functioning of several signaling pathways. Hypoactivation of estrogen receptor (ER) and hyperactivation of Hedgehog and PI3K/AKT/mTOR signaling cascades are involved in a transition to neoplasia, while the decreased activity of androgen receptor (AR) and Wnt pathways contribute to disease progression [ 111 ]. Detailed recognition of pathologic signaling at the molecular level provides the mechanistic background for novel therapeutic approaches ( Figure 3 ).…”

Section: Signal Transduction Pathways As Potential Therapeutic Targetsmentioning

confidence: 99%

cAMP-Dependent Signaling and Ovarian Cancer

Kilanowska

Ziółkowska

Stasiak

et al. 2022

Cells

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cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA and EPAC—it regulates gene expression and many cellular functions. PKA promotes the phosphorylation of cAMP response element-binding protein (CREB) which mediates gene transcription, cell migration, mitochondrial homeostasis, cell proliferation, and death. EPAC, on the other hand, is involved in cell adhesion, binding, differentiation, and interaction between cell junctions. Ovarian cancer growth and metabolism largely depend on changes in the signal processing of the cAMP-PKA-CREB axis, often associated with neoplastic transformation, metastasis, proliferation, and inhibition of apoptosis. In addition, the intracellular level of cAMP also determines the course of other pathways including AKT, ERK, MAPK, and mTOR, that are hypo- or hyperactivated among patients with ovarian neoplasm. With this review, we summarize the current findings on cAMP signaling in the ovary and its association with carcinogenesis, multiplication, metastasis, and survival of cancer cells. Additionally, we indicate that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer.

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Section: Signal Transduction Pathways As Potential Therapeutic Targetsmentioning

confidence: 99%

cAMP-Dependent Signaling and Ovarian Cancer

Kilanowska

Ziółkowska

Stasiak

et al. 2022

Cells

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“…On this scale, 0 corresponds to the lowest odds, and 100 corresponds to the highest odds in favor of active pathway activity. To identify aberrant STP activity, STP activity scores of healthy postmenopausal fallopian tube epithelium (post‐FTE) were used as a reference for normal activity 26 . Growing evidence suggests a tubal origin of serous borderline tumors and serous LGOC, like in HGSOC 27 .…”

Section: Methodsmentioning

confidence: 99%

“…Growing evidence suggests a tubal origin of serous borderline tumors and serous LGOC, like in HGSOC 27 . Post‐FTE scores were used because the hormonal status is similar to that of our study population 26 …”

Section: Methodsmentioning

confidence: 99%

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

Hendrikse

Ploeg

Kruis

et al. 2023

Cancer

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Background Advanced low‐grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. Methods Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. Results Patients who had normal ER STP activity had a progression‐free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. Conclusions Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

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“…2. Ligand dependency: (i) Auto-secretory ligand-dependent activation, in which tumor cells respond to increased expression of their HH ligands in a cell-autonomous manner (i.e., glioblastoma [ 201 ], neck squamous cell carcinoma [ 202 , 203 ], and lung [ 204 ], breast [ 205 , 206 ], ovarian [ 207 ], stomach [ 208 , 209 ], esophageal [ 210 ], pancreatic [ 211 ], and prostate cancers); (ii) Paracrine-ligand-dependent model, in which Hh ligands produced and released by tumor cells switch on HH signaling in the peripheral stroma, in turn facilitating tumor expansion and metastasis, and creating a positive feedback loop (i.e., prostate, ovarian [ 212 – 214 ], pancreatic [ 215 ] and colorectal cancers [ 216 , 217 ]); (iii) Reverse paracrine ligand-dependent signaling activation, indicates that Hh ligands are secreted from the stroma and received by tumor cells (i.e., multiple myeloma, lymphoma [ 218 ], and leukemia [ 219 , 220 ]). 3.…”

Section: Role In Cancer and Therapeutic Strategiesmentioning

confidence: 99%

The role of Hedgehog and Notch signaling pathway in cancer

Xia

Yang

et al. 2022

Mol Biomed

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Notch and Hedgehog signaling are involved in cancer biology and pathology, including the maintenance of tumor cell proliferation, cancer stem-like cells, and the tumor microenvironment. Given the complexity of Notch signaling in tumors, its role as both a tumor promoter and suppressor, and the crosstalk between pathways, the goal of developing clinically safe, effective, tumor-specific Notch-targeted drugs has remained intractable. Drugs developed against the Hedgehog signaling pathway have affirmed definitive therapeutic effects in basal cell carcinoma; however, in some contexts, the challenges of tumor resistance and recurrence leap to the forefront. The efficacy is very limited for other tumor types. In recent years, we have witnessed an exponential increase in the investigation and recognition of the critical roles of the Notch and Hedgehog signaling pathways in cancers, and the crosstalk between these pathways has vast space and value to explore. A series of clinical trials targeting signaling have been launched continually. In this review, we introduce current advances in the understanding of Notch and Hedgehog signaling and the crosstalk between pathways in specific tumor cell populations and microenvironments. Moreover, we also discuss the potential of targeting Notch and Hedgehog for cancer therapy, intending to promote the leap from bench to bedside.

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Signal transduction pathway activity in high-grade serous carcinoma, its precursors and Fallopian tube epithelium

Cited by 6 publications

References 50 publications

cAMP-Dependent Signaling and Ovarian Cancer

cAMP-Dependent Signaling and Ovarian Cancer

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

The role of Hedgehog and Notch signaling pathway in cancer

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