Autocrine PDGFR signaling promotes mammary cancer metastasis

Jechlinger, Martin; Sommer, Andreas; Moriggl, Richard; Seither, Peter; Kraut, Norbert; Capodiecci, Paola; Donovan, Michael P.; Cordon‐Cardo, Carlos; Beug, Hartmut; Grünert, Stefan

doi:10.1172/jci24652

Cited by 326 publications

(277 citation statements)

References 65 publications

(99 reference statements)

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“…PDGF is a major growth factor for mesenchymal cells. A potential autocrine/paracrine loop of PDGFA and PDGFRA is implicated in epithelial-mesenchymal interaction during development (Xu et al, 2005) and is involved in the metastatic potential of TGF-b-induced EMT in breast cancer cells (Jechlinger et al, 2006). Taken together, these data substantiate the role of an autocrine loop of PDGFA and PDGFRA in EMT, which underlies the pathogenesis of MCB and might also imply a novel application of STI571, an inhibitor of PDGFRA, to therapeutically interfere with metastasis in this cancer.…”

Section: Discussionmentioning

confidence: 52%

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Lien

Hsiao

Lin³

et al. 2007

Oncogene

187

156

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Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-agenome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

show abstract

Section: Discussionmentioning

confidence: 52%

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Lien

Hsiao

Lin³

et al. 2007

Oncogene

187

156

View full text Add to dashboard Cite

show abstract

“…2). [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Several types of cancers, particularly those derived from the ovary, prostate, breast, lung, brain, skin, and bone, express PDGFRa on the malignant cells themselves (Table 1). 22 In 1 experiment in which a human tumor array was probed with a cross-reactive polyclonal rabbit antibody to PDGFRa, PDGFRa expression was noted in approximately 95% of osteosarcomas and chondrosarcomas, in 77% of prostate cancers, in 52% of ovarian cancers, in 65% of breast cancers, and in 51% of lung cancers (N. Loizos, ImClone Systems, unpublished results).…”

Section: The Pdgf/pdgfr Axis In Cellular Signalingmentioning

confidence: 99%

“…59 Investigations in multiple cancer types have highlighted the relevance of both PDGF-activated tumor and supporting stromal cells in facilitating cancer growth and metastasis. [44][45][46][47][48][49][50][51]55,57,60 In some cases, specific autocrine or paracrine mechanisms that contribute to malignant progression have been suggested. In 1 experiment, NIH 3T3 cells were transformed when PDGF-A or PDGF-B gene expression was induced using a transfected promoter.…”

Section: The Pdgf/pdgfr Axis In Cellular Signalingmentioning

confidence: 99%

“…PDGFs can influence cancer growth and malignant angiogenesis through several mechanisms, including the activation of PDGFRa expressed on cancer cells, stromal fibroblasts, and vascular endothelial cells and by PDGF-induced production of vascular endothelial growth factor (VEGF) by stromal cells. [45][46][47][48][49][50][51][52][53][54][55]57,60 The asterisk indicates that Table 1 required for the development of malignant stroma, 46 a separate study indicated that the induction of PDGF-CC expression in melanoma cells led to accelerated tumor growth through the activation of PDGFRa. 47 In the latter study, the exclusive expression of PDGFRa on cancerassociated stromal fibroblasts illuminated a paracrine mechanism of stromal-regulated melanoma tumor growth.…”

Section: The Pdgf/pdgfr Axis In Cellular Signalingmentioning

confidence: 99%

“…It also has been demonstrated that PDGF/ PDGFRa-associated autocrine or paracrine mechanisms that involve tumor and stroma similarly play important roles in the growth of hepatocellular cancers 48,49 and lung cancers, 51 in facilitating bone metastasis in prostate cancers, 60 and in the metastatic spread of lung and breast cancers. 45,57 It also has been established that an intact PDGF/ PDGFRa axis is required for vascular endothelial growth factor (VEGF) production by tumor stroma and for the regulation of malignant angiogenesis in tumors that are resistant to antiangiogenic treatment. [52][53][54] The former was demonstrated in an elegant experiment in which VEGF-null fibrosarcomas grown in mice required the recruitment of PDGFRa-expressing stromal fibroblasts for VEGF production, angiogenesis, and tumorigenesis.…”

Section: The Pdgf/pdgfr Axis In Cellular Signalingmentioning

confidence: 99%

See 2 more Smart Citations

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

Shah

Loizos²,

Youssoufian³

et al. 2010

Cancer

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A large body of evidence suggests that the platelet-derived growth factor (PDGF) family and associated receptors are potential targets in oncology therapeutic development because of their critical roles in the proliferation and survival of various cancers and in the regulation and growth of the tumor stroma and blood vessels. Several small molecules that nonspecifically target the PDGF signaling axis are in current use or development as anticancer therapies. However, for the majority of these agents, PDGF and its receptors are neither the primary targets nor the principal mediators of anticancer activity. IMC-3G3, a fully human monoclonal antibody of the immunoglobulin G subclass 1, specifically binds to the human PDGF receptor a (PDGFRa) with high affinity and blocks PDGF ligand binding and PDGFRa activation. The results of preclinical studies and the frequent expression of PDGFRa in many types of cancer and in cancer-associated stroma support a rationale for the clinical development of IMC-3G3. Currently, IMC-3G3 is being evaluated in early clinical development for patients with several types of solid malignancies. Cancer 2010;116(4 suppl):1018-26.

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Circulating exosomalmiR‐363‐5pinhibits lymph node metastasis by downregulatingPDGFBand serves as a potential noninvasive biomarker for breast cancer

et al. 2021

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The sentinel lymph node (LN) biopsy is currently the standard procedure for clinical LN-negative breast cancer (BC) patients, but is prone to false-negative results and complications. Thus, an accurate noninvasive approach for LN staging is urgently needed in clinical practice. Here, circulating exosomal miRNA expression profiles in peripheral blood from BC patients and age-matched healthy women were obtained and analyzed. We identified an exosomal miRNA, miR-363-5p, that was significantly downregulated in exosomes from plasma of BC patients with LN metastasis and exhibited a consistent decreasing trend in tissue samples from multiple independent datasets. Plasma exosomal miR-363-5p achieved high diagnostic performance in distinguishing LN-positive patients from LN-negative patients.The high miR-363-5p level was significantly correlated with improved overall survival. Functional assays demonstrated that exosomal miR-363-5p modulates platelet-derived growth factor (PDGF) signaling activity by targeting PDGFB to inhibit cell proliferation and migration. Our study is the first to reveal that plasma exosomal miR-363-5p plays a suppressor role in BC and has the potential for noninvasive LN staging and prognosis prediction of BC.

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Autocrine PDGFR signaling promotes mammary cancer metastasis

Cited by 326 publications

References 65 publications

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

Circulating exosomalmiR‐363‐5pinhibits lymph node metastasis by downregulatingPDGFBand serves as a potential noninvasive biomarker for breast cancer

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