EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling

DeHaan, Alyse M.; Wolters, Natalie; Keller, Evan T.; Ignatoski, Kathleen M. Woods

doi:10.1002/pros.20903

Cited by 40 publications

(31 citation statements)

References 36 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TGF-α is one of the two EGFR ligands expressed in prostate cancer. Previous studies have demonstrated that with the disease progresses to more advanced stages, TGF-α is the predominant ligand for EGFR (33,34). Moreover, cell lines derived from different prostatic cancers and their metastases, including DU145 overexpress TGF-α (35,36), and TGF-α/EGFR autocrine loop is a hallmark of PCa invasion and progression (37,38).…”

Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

show abstract

Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…Numerous gene expression profiling analyses have allowed researchers to identify specific molecular signatures that may be associated with a high potential of PC cells detected at primary tumors to undergo metastatic spread and establish their homing at specific distant tissues as well as the molecular changes that may occur at the predestinated metastatic sites (23,153,154). In particular, a loss of PTEN, p53 and breast cancer type 1 (BRCA1) combined with an upregulation of EGFR, hedgehog, TGF-β/TGF-βR receptor, ECM components/integrins and SDF-1/ CXCR4 and downstream effectors such as PI3K/Akt, small GTPase Rac-1, mitogenactivated protein kinases, NF-κB, MIC-1 and Rho are often detected in metastatic PC cells (11,135,153,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166). It has also been shown that the migration and engraftment of metastatic PC cells in bones, the most common site of PC metastasis, as well as other distant tissues may be mediated in part through the formation of chemoattractant gradients such as SDF-1 released by host endothelial cells and fibroblasts at distant tissues that specifically attract the metastatic PC cells overexpressing CXCR4 (Figure 1) (23,122,(167)(168)(169).…”

Section: Frequent Gene Products and Molecular Pathways Altered In Metmentioning

confidence: 99%

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Mimeault

Batra

2011

Mol Med

View full text Add to dashboard Cite

Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

show abstract

“…Significant roles for the ErbB family receptors (EGFR (HER1), HER2, HER3 and HER4) have been suggested in prostate tumorigenesis and progression for a number of years, but the molecular mechanisms by which ErbB family members support the disease progression and metastasis is not fully understood. Aberrant activities of HER2 and EGFR have also been associated with development of castration resistant disease, possibly due to compensation for the loss of androgen signaling (2–5). Like prostate cancer, breast cancer is a hormone sensitive/refractory disease, and both share common sites of metastases, such as bone.…”

Section: Introductionmentioning

confidence: 99%

HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone

et al. 2017

View full text Add to dashboard Cite

Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites.

show abstract

EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling

Cited by 40 publications

References 36 publications

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone

Contact Info

Product

Resources

About