Expression of C-kit and Platelet-Derived Growth Factor Receptors in Ovarian Granulosa Cell Tumors

Rocconi, Rodney P.; Matthews, Kellie S.; Kimball, Kristopher J.; Conner, Michael; Baker, Allyson C.; Barnes, Mack N.

doi:10.1177/1933719108317584

Cited by 13 publications

(11 citation statements)

References 24 publications

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“…In ovarian carcinoma, some studies have examined the biological role of PDGFRa and its efficacy as a therapeutic target. Stimulation of PDGFRa with its ligand, such as PDGF-AA, increases cell proliferation and activation of AKT and MAPK signaling, and neutralizing PDGFRa inhibited these signaling effects [17]. PDGFRA is verified as the direct target gene of miR-140-5p in ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 92%

miR-140-5p inhibits ovarian cancer growth partially by repression of PDGFRA

Hong

Chen²,

et al. 2015

Biomedicine & Pharmacotherapy

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Section: Discussionmentioning

confidence: 92%

miR-140-5p inhibits ovarian cancer growth partially by repression of PDGFRA

Hong

Chen²,

et al. 2015

Biomedicine & Pharmacotherapy

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“…Granulosa cell tumors (GCTs) are generally considered indolent tumors, but are associated with late recurrences, at which time the survival rate is significantly shortened (29). Previous studies have demonstrated the expression of PDGF receptors in both adult and juvenile forms of GCTs (30, 31), but the function or expression of PDGFA in JGCTs has not been reported. This tumor type is rare, and though our samples size is small, the majority of tumor samples used in the present study exhibited expression of PDGFA , PDGFRA and PDGFRB, suggesting that autocrine PDGF receptor stimulation could contribute to the tumor growth.…”

Section: Discussionmentioning

confidence: 94%

BMP-specific SMADs function as novel repressors of PDGFA and modulate its expression in ovarian granulosa cells and tumors

et al. 2012

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Platelet-derived growth factor alpha (PDGFA) is frequently upregulated in various cancers and thought to function as a key player in the development and progression of tumor growth by regulating aspects of cell proliferation, angiogenesis, and metastasis. However, the mechanism by which it is upregulated is not fully understood. Previously, we demonstrated that conditional deletion of two transcription factors that signal for the bone morphogenetic proteins (Smad1 and Smad5) in ovarian granulosa cells causes metastatic granulosa cell tumors in female mice and phenocopies human juvenile granulosa cell tumors (JGCTs). Smad1/5 double conditional knockout tumors, as well as human JGCTs, are highly vascularized, hemorrhagic, and mitotically active. Expression analysis of these tumors and their metastases revealed a significant upregulation of key proliferation and pro-angiogenic factors such as Pdgfa, Pdgfb, and Vegf. We examined whether these genes were direct targets of SMAD1 and SMAD5. Knockdown of SMAD1 and SMAD5 in mouse primary granulosa cells and a human granulosa cell tumor-derived cell line (COV434) resulted in upregulation of PDGFA, but not PDGFB nor VEGF. We identified several putative SMAD1/5 binding sites in the PDGFA promoter, and chromatin immunoprecipitation and reporter assays demonstrated that SMAD1/5 interact with the PDGFA promoter to regulate its activity. Further, SMAD1/5 antagonize the activity of the transcription factor Sp1, a well-known positive regulator of PDGFA, by inhibiting its occupancy at a key regulatory site on the proximal PDGFA promoter. Collectively, our studies establish that loss of SMAD1/5 leads to upregulation of PDGFA in ovarian granulosa cells, and that a novel regulatory interaction exists between the BR-SMADs and Sp1 in controlling PDGFA expression during granulosa cell tumorigenesis.

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“…GCT also express a panel of molecular targets, like EGFR, c‐kit, PDGFRa‐b, c‐abl, m‐TOR and VEGF, but not others like Her‐2/neu. Anti‐EGFR, m‐TOR inhibitors and anti‐VEGF have been proposed as targeted therapies in GCT, as drugs acting against tyrosine kinase (PDGFR, c‐kit, c‐abl), with a reported response rate of 38% for bevacizumab 5–10 . Imatinib mesylate is a molecule inhibiting the tyrosine kinase c‐abl, c‐kit, PDGFR‐a, PDGFR‐b, leading cells to pro‐apoptotic changes.…”

Section: Discussionmentioning

confidence: 99%

“…Imatinib mesylate is a molecule inhibiting the tyrosine kinase c‐abl, c‐kit, PDGFR‐a, PDGFR‐b, leading cells to pro‐apoptotic changes. It has first been used to treat Ph‐positive chronic myeloid leukemia (c‐abl), and also demonstrates to be active against gastrointestinal stromal tumor (GIST) (c‐kit) 5 . The in vivo use of imatinib in GCT was first reported by Jakob et al 11 .…”

Section: Discussionmentioning

confidence: 99%

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Third‐line chemotherapy with tyrosine kinase inhibitor (imatinib mesylate) in recurrent ovarian granulosa cell tumor: Case report

Raspagliesi

Martinelli

Grijuela

et al. 2011

J of Obstet and Gynaecol

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Granulosa cell tumors (GCT) of the ovary represent less than 5% of malignant ovarian tumors. Primary treatment of GCT is surgery. GCT present indolent growth and also tend to relapse many years after diagnosis. Radiotherapy, chemotherapy and hormonal therapy are of little benefit. We report a case of a 60-year-old woman with a heavily pretreated recurrent, c-kit positive, GCT of the ovary who underwent an experimental therapy with imatinib, a tyrosine kinase inhibitor. Imatinib (400 mg/day during the first 2 months; 800 mg/day after) was given, without notable side-effects. Monthly positron emission tomography-computed tomography scan evaluations were performed revealing a marked reduction of disease after 6 months of treatment. To our knowledge this is the first case of highly recurrent and unresponsive GCT of the ovary responding to imatinib. Further studies evaluating this drug in recurrent and/or aggressive GCT are warranted.

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Expression of C-kit and Platelet-Derived Growth Factor Receptors in Ovarian Granulosa Cell Tumors

Abstract: The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.

Cited by 13 publications

References 24 publications

miR-140-5p inhibits ovarian cancer growth partially by repression of PDGFRA

miR-140-5p inhibits ovarian cancer growth partially by repression of PDGFRA

BMP-specific SMADs function as novel repressors of PDGFA and modulate its expression in ovarian granulosa cells and tumors

Third‐line chemotherapy with tyrosine kinase inhibitor (imatinib mesylate) in recurrent ovarian granulosa cell tumor: Case report

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