In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis
Abstract
:1. Introduction
2. mRNA Level Studies
3. Protein Expression
4. Tissue Electrolytes
5. In Vivo Animal Tests
6. Clinical Studies
7. Conclusions and Future Perspective
Funding
Conflicts of Interest
References
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Carcinoma | VGSC Subtype(s) | Comment(s) | Reference(s) |
---|---|---|---|
Breast | nNav1.5 (and (n)Nav1.7) | Dominant at mRNA level and functional contribution to invasiveness/metastasis verified in vitro and in vivo | [9,10,11,12] |
Colon | nNav1.5 | Dominant at mRNA level and expressed early in invasiveness; functional contribution to invasiveness verified in vitro and in vivo | [13,14,15] |
Prostate | (n)Nav1.7 (and Nav1.6) | Dominant at mRNA level; specific functional contribution to invasiveness tested using peptide toxins | [8,16,17,18] |
Non-small cell lung carcinoma (NSCLC) | Nav1.7 | Dominant at mRNA level; potentiation of invasiveness demonstrated by use of siRNA | [19] |
Mesothelioma | Nav1.2, Nav1.6, and Nav1.7 | VGSC activity shown to promote migration in vitro, but the subtype(s) responsible not determined | [20] |
Cervical | (n)Nav1.6 | Dominant at mRNA level; over-expression potentiated invasiveness | [21,22] |
Stomach | Nav1.7 | Dominant at mRNA level; silencing suppressed tumour growth in mouse model in vivo | [23] |
Ovary | Nav1.5 | Dominant at mRNA level; E3 antibody suppressed in vivo growth and in vitro invasiveness | [24,25] |
Melanoma | Nav1.5 | Expression induced membrane potential depolarization and inhibited Ca2+ uptake | [26] |
Oral squamous cell carcinoma | Nav1.5 | siRNA confirmed in vitro potentiation of proliferation and invasiveness | [27] |
Astrocytoma | nNav1.5 | siRNA confirmed in vitro potentiation of proliferation and invasiveness | [28] |
Neuroblastoma | nNav1.5 | Where ‘neonatal’ Nav1.5 splicing was first described, but role in cancer not investigated | [29] |
Endometrium | Nav1.7 | Channel block attenuated in vitro cell invasion; expression was associated (i) positively with tumour size and local lymph node metastasis, and (ii) negatively with survival (5–10 years) | [30] |
VGSC Property | Clinical Consequence(s) | Reference(s) |
---|---|---|
Expression much higher in strongly vs. weakly metastatic cancers (by up to several orders of magnitude at mRNA level) | Potential functional diagnostic molecular biomarker | e.g., [9,16,40] |
Expression is early and upstream of the genes driving invasiveness | Potential functional ‘early’ marker, ideal for diagnostics | [14] |
Upregulation maintained at protein and functional (signalling) levels | Diagnostics can be extended to conventional immunohistochemistry and even clinical imaging of tissue sodium possibly resulting from channel activity (e.g., 23Na-MRI); expression can be used to determine treatment strategy and efficacy | [9,16,57,65,66] |
Gene/protein expressed in neonatal splice form in several carcinomas; targetable by antibody | Diagnostics can be made even more specific; antibody can also be used as a drug (i) to block channel activity/metastasis and/or (ii) kill tumour cells (in antibody-drug conjugate mode) | [9,10,56] |
Activity-dependent regulation (positive feedback)—VGSC blockers suppress both channel activity and expression | VGSC blockage would suppress both activity and expression of the channel, thereby providing long-term benefit to cancer patients taking VGSC drugs | [60,116] |
Promotes a range of cellular behaviours integral to the metastatic cascade in vitro, as well as metastasis per se in vivo | Therapeutic potential—possible ‘repurposing’ of existing VGSC drugs, INaP blockers (as well as novel antibody), possibly with minimal side effects | [11,12,36,114] |
Functional expression under the control of steroid hormones and growth factors | Therapeutic potential extended to ‘combination’ treatments | [19,61] |
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Djamgoz, M.B.A.; Fraser, S.P.; Brackenbury, W.J. In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis. Cancers 2019, 11, 1675. https://doi.org/10.3390/cancers11111675
Djamgoz MBA, Fraser SP, Brackenbury WJ. In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis. Cancers. 2019; 11(11):1675. https://doi.org/10.3390/cancers11111675
Chicago/Turabian StyleDjamgoz, Mustafa B. A., Scott P. Fraser, and William J. Brackenbury. 2019. "In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis" Cancers 11, no. 11: 1675. https://doi.org/10.3390/cancers11111675