Modeling Selective Elimination of Quiescent Cancer Cells from Bone Marrow

Cavnar, Stephen P.; Rickelmann, Andrew D.; Meguiar, Kaille F.; Xiao, Annie; Dosch, Joseph S.; Leung, Brendan M.; Lesher‐Pérez, Sasha Cai; Chitta, Shashank; Luker, Kathryn E.; Takayama, Shuichi; Luker, Gary D.

doi:10.1016/j.neo.2015.08.001

Cited by 29 publications

(54 citation statements)

References 43 publications

(49 reference statements)

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“…This extends prior reports that mixed HS5/hFOB/breast cancer cell co-culture inhibited breast cancer growth[19] [20]. …”

Section: Discussionsupporting

confidence: 89%

“…Secreted components from that mixture of cells were sufficient to inhibit growth[19]. HS5 cells also arrested T47 and MDA-MB-231 cells in spheroid co-culture [20]. In prostate cancer cells, paracrine BMP7 signaling by HS5 cells induced a dormant state, although a paracrine anti-proliferative effect of this stromal line on breast cancer cells has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals

Huang

Woods

Normolle

et al. 2016

Breast Cancer Res Treat

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Purpose Breast cancers have a poorer prognosis if estrogen receptor expression was lost during recurrence. It is unclear whether this conversion is cell autonomous or whether it can be promoted by the microenvironment during cancer dormancy. We explored the ability of marrow-derived stromal cell lines to arrest co-cultured breast cancer cells and suppress estrogen receptor alpha (ER) expression during arrest, facilitating the emergence of estrogen-independent breast cancer clones. Methods Cancer cell growth, ER protein, microRNA and mRNA levels were measured in breast cancer cell lines exposed to conditioned medium from marrow stromal lines in the presence and absence of estrogen and of signaling pathway modulators. Results We demonstrate that paracrine signaling from the stromal cell line HS5 downregulated ER in T47D and MCF7 breast cancer cells. This occurred at the mRNA level and also through decreased ER protein stability. Additionally, conditioned medium (CM) from HS5 arrested the breast cancer cells in G0/G1 in part through interleukin-1 (IL1) and inhibited cancer cell growth despite activation of proliferative pathways (Erk and AKT) by the CM. Similar findings were observed for CM from the hFOB 1.19 osteoblastic cell line but not from two other fibroblastic marrow lines, HS27A and KM101. HS5-CM inhibition of MCF7 proliferation could not be restored by exogenous ER, but was restored by the IL1-antagonist IL1RA. In the presence of IL1RA, HS5-CM activation of AKT and Erk enabled the outgrowth of breast cancer cells with suppressed ER that were fulvestrant-resistant and estrogen-independent. Conclusions We conclude that marrow-derived stromal cells can destabilize estrogen receptor protein to convert the ER status of growth-arrested ER+ breast cancer cell lines. The balance between stromal pro- and anti-proliferative signals controlled the switch from a dormant phenotype to estrogen-independent cancer cell growth.

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“…This extends prior reports that mixed HS5/hFOB/breast cancer cell co-culture inhibited breast cancer growth[19] [20]. …”

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals

Huang

Woods

Normolle

et al. 2016

Breast Cancer Res Treat

View full text Add to dashboard Cite

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“…This implies, that this organ might have a high ability to clear disseminated colon cancer cells or to prevent their proliferation. During the last years these findings have led to a hypothesis of tumor cell dormancy and tumor stem cells that reside in the bone marrow niche and recirculate after years to form distant metastases [26–28]. Recently, we have been able to show that patients with colorectal liver metastases and detectable DTC in the bone marrow at the time of liver surgery, had an unfavorable prognosis after complete liver metastases resection [29].…”

Section: Discussionmentioning

confidence: 99%

Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients – a prospective study

et al. 2017

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BackgroundDetection of circulating (CTC) or disseminated tumor cells (DTC) has been associated with negative prognosis and outcome in patients with colorectal cancer, though testing for these cells is not yet part of clinical routine. There are several different methodological approaches to detect tumor cells but standardized detection assays are not implemented so far.MethodsIn this prospective monocentric study 299 patients with colon cancer were included. CTC and DTC were detected using CK20 RT-PCR as well as immunocytochemistry staining with anti-pan-keratin and anti-EpCAM antibodies. The primary endpoints were: Evaluation of CTC and DTC at the time of surgery and correlation with main tumor characteristics and overall (OS) and disease free survival (DFS).ResultsPatients with detectable CTC had a 5-year OS rate of 68% compared to a 5-year OS rate of 85% in patients without detectable CTC in the blood (p = 0.002). Detection of DTC in the bone marrow with CK20 RT-PCR was not associated with a worse OS or DFS. Detection of pan-cytokeratin positive DTC in the bone marrow correlated with a significantly reduced 5-year OS rate (p = 0.048), but detection of DTC in the bone marrow with the anti-EpCAM antibody did not significantly influence the 5-year OS rate (p = 0.958). By multivariate analyses only detection of CTC with CK20 RT-PCR in the blood was revealed to be an independent predictor of worse OS (HR1.94; 95% CI 1.0–3.7; p = 0.04) and DFS (HR 1.94; 95% CI 1.1–3.7; p = 0.044).ConclusionsDetection of CTC with CK20 RT-PCR is a highly specific and independent prognostic marker in colon cancer patients. Detection of DTC in the bone marrow with CK20 RT-PCR or immunohistochemistry with anti-EpCAM antibody is not associated with a negative prognostic influence.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3035-1) contains supplementary material, which is available to authorized users.

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“…Detail procedures for stable transfection of MDA-MB-231 cells with click beetle green luciferase were similar with a previous report [30]. cbgLuc-MDA-MB-231 cells were maintained in DMEM medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum at 37 °C with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 96%

In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide

et al. 2016

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Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ~ 120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. 64 Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of 64 Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript when compared with that of non-targeted GO conjugates ( 64 Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics. Graphical Abstract KeywordsNano-graphene oxide (GO); Angiogenesis; Follicle-stimulating hormone receptor (FSHR); Breast cancer metastasis; Positron emission tomography (PET); Image-guided drug delivery

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Modeling Selective Elimination of Quiescent Cancer Cells from Bone Marrow

Cited by 29 publications

References 43 publications

Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals

Downregulation of estrogen receptor and modulation of growth of breast cancer cell lines mediated by paracrine stromal cell signals

Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients – a prospective study

In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide

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