Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth

Mainetti, Leandro E.; Zhe, Xiaoning; Diedrich, Jonathan D.; Saliganan, Allen; Cho, Won J in; Cher, Michael L.; Heath, Elisabeth I.; Fridman, Rafael; Kim, Hyeong Reh C hoi; Bonfil, R. Daniel

doi:10.1002/ijc.28948

Cited by 25 publications

(17 citation statements)

References 46 publications

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“…1 ). Similar observations were previously made by others for pancreatic [11] , NSCLC [38] or prostate cancer cells [39] . Beside this variation we observed that there were always one or two cell lines with extreme values, as for instance for H520 cells characterized by an extreme over-expression of SCF, and H23 and LnCap both showing a very low expression when compared to the other cell lines ( Fig.…”

Section: Discussionsupporting

confidence: 91%

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed

Eberle

Leinberger

Saulich

et al. 2017

Clinical and Translational Radiation Oncology

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Background and purposeThe SCF/c-Kit pathway is often overexpressed in human tumors leading to an enhanced tumorigenesis, proliferation and migration. It was now tested for NSCLC and prostate cancer cells growing in 2D and 3D whether the inhibition of this pathway can be used to achieve a significant radiosensitization and whether a respective biomarker may be identified.Material and methodsExperiments were performed with different cancer cell lines (NSCLC: H23, H520, H226, H1975 and PrCa: DU145) growing either under 2D or 3D conditions. Expression of SCF and c-Kit was determined by RT-PCR and Western blot, SCF was knocked down by siRNA, c-Kit was inhibited by ISCK03 inhibitor and cell survival was determined by colony formation assay.ResultsThere is a profound variation in the expression of both c-Kit and SCF with no association between each other. Neither levels did correlate with the respective cellular radiosensitivity determined for 2D or 3D with only a trend seen for SCF. Knock-down of SCF was generally found to result in no or only minor reduction of plating efficiency or cellular radioresistance. A significant reduction was only obtained for H520 cells characterized by an extreme over-expression of SCF. The inhibition of c-Kit by a specific inhibitor was also found to result only in minor radiosensitization.ConclusionGenerally, the SCF/c-Kit pathway does not have a dominant effect on both, cell survival and radioresponse and, as a consequence, knockdown of this pathway does not result in a strong effect on radioresistance, except when SCF is strongly over-expressed.

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Section: Discussionsupporting

confidence: 91%

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed

Eberle

Leinberger

Saulich

et al. 2017

Clinical and Translational Radiation Oncology

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“…[21], [52], [57] CD117 expression in many cancers is associated with shorter disease survival and metastasis and is increased with cancer progression in prostate cancer patients with the highest levels of CD117 staining seen in bone metastases. [21], [57]- [59] However, the opposite is true in myeloid/erythroid cancers, whose patients have improved or unchanged prognosis when CD117 is expressed. [60] This may be partially due to biological differences between hematologic malignancies and solid tumors in Harris 18 which some genes and miRNA have opposite functions.…”

Section: Discussionmentioning

confidence: 99%

CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

Harris

Shi

Foster

et al. 2018

Preprint

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Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/ckit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used LNCaP-C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population.Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.Harris 3

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“…Previous studies have reported LCM and DNA sequencing from a frozen bone metastasis of a mCRPC patient [ 49 ], or gene expression analysis of total RNA directly obtained from snap-frozen bone marrow biopsies largely replaced by tumor [ 50 ] or frozen bone metastatic cores isolated at autopsy [ 12 , 13 , 51 , 52 ]. However, in addition to our earliest analysis in a few PCa bone metastasis [ 53 ], the present study is the only report that, to the best of our knowledge, uses LCM and aRNA amplification for gene analysis of limited number of tumor cells microdissected from FFPE BMBx obtained from living mCRPC patients. In spite of better RNA recovery and quality ascribed to frozen tissue [ 43 , 44 , 54 ], we found that its use as homogenate might be inadequate for gene expression analysis of PCa bone micrometastasis, due to dilution of PCa-specific genes by other genes expressed predominantly by bone cells.…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis of bone metastasis and circulating tumor cells from metastatic castrate-resistant prostate cancer patients

et al. 2016

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BackgroundCharacterization of genes linked to bone metastasis is critical for identification of novel prognostic or predictive biomarkers and potential therapeutic targets in metastatic castrate-resistant prostate cancer (mCRPC). Although bone marrow core biopsies (BMBx) can be obtained for gene profiling, the procedure itself is invasive and uncommon practice in mCRPC patients. Conversely, circulating tumor cells (CTCs), which are likely to stem from bone metastases, can be isolated from blood. The goals of this exploratory study were to establish a sensitive methodology to analyze gene expression in BMBx and CTCs, and to determine whether the presence or absence of detectable gene expression is concordant in matching samples from mCRPC patients.MethodsThe CellSearch® platform was used to enrich and enumerate CTCs. Low numbers of PC3 prostate cancer (PCa) cells were spiked into normal blood to assess cell recovery rate. RNA extracted from recovered PC3 cells was amplified using an Eberwine-based procedure to obtain antisense mRNA (aRNA), and assess the linearity of the RNA amplification method. In this pilot study, RNAs extracted from CTCs and PCa cells microdissected from formalin-fixed paraffin-embedded BMBx, were amplified to obtain aRNA and assess the expression of eight genes functionally relevant to PCa bone metastasis using RT-PCR.ResultsRNAs were successfully extracted from as few as 1–5 PCa cells in blood samples. The relative expression levels of reference genes were maintained after RNA amplification. The integrity of the amplified RNA was also demonstrated by RT-PCR analysis using primer sets that target the 5′-end, middle, and 3′-end of reference mRNA. We found that in 21 out of 28 comparisons, the presence or absence of detectable gene expression in CTCs and PCa cells microdissected from single bone lesions of the same patients was concordant.ConclusionsThis exploratory analysis suggests that aRNA amplification through in vitro transcription may be useful as a method to detect gene expression in small numbers of CTCs and tumor cells microdissected from bone metastatic lesions. In some cases, gene expression in CTCs and BMBxs was not concordant, raising questions about using CTC gene expression to make clinical decisions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0829-5) contains supplementary material, which is available to authorized users.

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Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth

Cited by 25 publications

References 46 publications

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed

In cancer cell lines inhibition of SCF/c-Kit pathway leads to radiosensitization only when SCF is strongly over-expressed

CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

Gene expression analysis of bone metastasis and circulating tumor cells from metastatic castrate-resistant prostate cancer patients

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