Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides

Patel, Himatkumar V.; Ramkissoon, Shakti; Patel, Prem; Rameshwar, Pranela

doi:10.1073/pnas.0506351102

Cited by 62 publications

(116 citation statements)

References 28 publications

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“…For instance, until recently, little attention has been given to the different splice variants of NK1R. Previous studies pointed out the central role of NK1R-tr in breast cancer (104,105). Likewise, Gillespie et al analyzed NK1R-tr and NK1R-fl in colitis-associated cancer and found that it was the expression of NK1R-tr alone that predicted the progression from quiescent colitis to highgrade dysplasia and cancer (106).…”

Section: Therapeutic Innovations In Hepatoblastoma the Nk1r As A Tumomentioning

confidence: 99%

Therapeutic Innovations for Targeting Hepatoblastoma

Garnier

Ilmer

Kappler

et al. 2016

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Section: Therapeutic Innovations In Hepatoblastoma the Nk1r As A Tumomentioning

confidence: 99%

Therapeutic Innovations for Targeting Hepatoblastoma

Garnier

Ilmer

Kappler

et al. 2016

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“…Cytokine protein analyses were performed as described (22). Briefly, RayBio Cytokine Ab Arrays 3 and 5 membranes were incubated for 1 h in media, followed by consecutive incubations with biotin-conjugated cytokine Abs and HRP-streptavidin.…”

Section: Cytokine Microarraysmentioning

confidence: 99%

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Patel

Meyer

Greco

et al. 2010

The Journal of Immunology

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354

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Mesenchymal stem cells (MSCs) have been shown to support breast cancer growth. Because MSCs also increase the frequency of regulatory T cells (Tregs), this study tested the hypothesis that human MSCs, via Tregs, protect breast cancer cells (BCCs) from immune clearance MSCs suppressed the proliferation of PBMCs when the latter were exposed to gamma-irradiated BCCs. Similarly, MSCs showed significant inhibition of PBMC migration toward BCCs and a corresponding decrease in CXCL12. MSCs also inhibited NK cell and CTL functions, which correlated with reduced numbers of CD8+ and CD56+ cells compared with parallel cultures without MSCs. The reduced NK and CTL activities correlated with a decrease in intracellular and secreted granzyme B. To explain these immunosuppressive findings, we compared Treg levels after coculture with MSCs and found an ∼2-fold increase in Tregs, with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-β1 was largely responsible for the increase in Tregs based on knockdown studies. In the presence of Treg depletion, PBMC proliferation and effector functions were partially restored. Together, these studies show an MSC-mediated increase in Tregs in cocultures of PBMCs and BCCs. The results could be explained, in part, by the increase in Th2-type cytokines and MSC-generated TGF-β1. These findings demonstrate immune protection by MSCs to BCCs. The reduction in immune cell proliferation and recruitment mediated by MSCs has implications for treatment of breast cancer with chemotherapy.

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“…Compared with full-length (fl-TACR1), tr-NK1R lacks 96 amino acids at the cytoplasmic C-terminus of the receptor that are responsible for intracellular signal transduction. Although this splice variant is considered to be able to couple G proteins, it exhibits decreased efficiency with respect to internalization and desensitization (8,(13)(14)(15). The net result of this is a decreased ability for negative feedback inhibition, allowing constant activation despite saturation of the receptor complex (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

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Abstract. The substance P (SP; also known as TAC1)/neurokinin-1 receptor (NK1R; also known as TACR1) complex is a critical part in the development of cancer. Therefore, NK1R antagonists, such as the clinical drug aprepitant, are currently under investigation as future anticancer agents. In a previous study, NK1R (TACR1) was identified as a potent anticancer target in hepatoblastoma (HB). However, little is known regarding the exact distribution of this target among HB subsets and whether it correlates with clinical features and prognosis. In the present study, mRNA was isolated from 47 children with HB, and reverse transcription-quantitative polymerase chain reaction was performed on the samples to analyze the expression of full-length-TACR1 (fl-TACR1) and truncated-TACR1 (tr-TACR1). These data were correlated with data obtained from 9 tumor-free controls, as well as with the presence of metastasis, PRETEXT, vascular invasion, histology, age of diagnosis, multifocality, CTNNB1 mutation, gender and overall survival. Additionally, the present study investigated a recently described 16-gene signature characteri zing HB known to correlate with prognosis. Compared with tumor-free liver tissue, tumorous tissue expressed TACR1 significantly higher for the truncated version (P=0.0301), and by trend also for the full-length version. Accordingly, the expression of fl-TACR1 correlated with the expression of the truncated version (P=0.0074). Furthermore, a low expression of fl-TACR1 correlated with characteristics of the 16-gene signature known to predict prognosis (P=0.0222). However, there was no correlation between tr-TACR1 and the tumor characteristics investigated, including outcome, although a clear trend was observed for some tumor characteristics. The current results reinforced the previously described findings that in HB, tr-TACR1 is overexpressed compared with tumor-free liver tissue. Furthermore, to the best of our knowledge, the present study demonstrated for the first time that tr-TACR1 is expressed ubiquitously among the different subsets of HB. Therefore, NK1R may serve as a potent anticancer target in a large variety of patients with HB, independent of tumor biology and clinical stage.

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Transformation of breast cells by truncated neurokinin-1 receptor is secondary to activation by preprotachykinin-A peptides

Abstract: breast cancer ͉ cytokines ͉ bone marrow metastasis ͉ substance P ͉ tachykinin

Cited by 62 publications

References 28 publications

Therapeutic Innovations for Targeting Hepatoblastoma

Therapeutic Innovations for Targeting Hepatoblastoma

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

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