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Reversing the Tumor Target: Establishment of a Tumor Trap.

ABSTRACT: Despite the tremendous progress made in the field of cancer therapy in recent years, certain solid tumors still cannot be successfully treated. Alongside classical treatments in the form of chemotherapy and/or radiotherapy, targeted treatments such as immunotherapy that cause fewer side effects emerge as new options in the clinics. However, these alternative treatments may not be useful for treating all types of cancers, especially for killing infiltrative and circulating tumor cells (CTCs). Recent advances pursue the trapping of these cancer cells within a confined area to facilitate their removal for therapeutic and diagnostic purposes. A good understanding of the mechanisms behind tumor cell migration may drive the design of traps that mimic natural tumor niches and guide the movement of the cancer cells. To bring this trapping idea into reality, strong efforts are being made to create structured materials that imitate myelinated fibers, blood vessels, or pre-metastatic niches and incorporate chemical cues such as chemoattractants or adhesive proteins. In this review, the different strategies used (or could be used) to trap tumor cells are described, and relevant examples of their performance are analyzed.

SUBMITTER: Najberg M

PROVIDER: S-EPMC6699082 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Reversing the Tumor Target: Establishment of a Tumor Trap.

Najberg Mathie M Haji Mansor Muhammad M Boury Frank F Alvarez-Lorenzo Carmen C Garcion Emmanuel E

Frontiers in pharmacology 20190812

Despite the tremendous progress made in the field of cancer therapy in recent years, certain solid tumors still cannot be successfully treated. Alongside classical treatments in the form of chemotherapy and/or radiotherapy, targeted treatments such as immunotherapy that cause fewer side effects emerge as new options in the clinics. However, these alternative treatments may not be useful for treating all types of cancers, especially for killing infiltrative and circulating tumor cells (CTCs). Rec ...[more]

PMID: 31456685

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Project description:In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy. Using computational modeling and optimization, we aimed at reversing the pathological characteristics and restoring normal neural function by altering ion channel properties. We identified two key aspects of neural dysfunction in epileptogenesis: an enhanced response to synaptic input in general and to highly synchronized synaptic input in particular. In previous studies, we showed that the potassium channel K(A) played a major role in neural responses to highly synchronized input. It was therefore selected as the target upon which modulators would act. In biophysical simulations, five experimentally characterized endogenous modulations on the K(A) channel were included. Relative concentrations of these modulators were controlled by a numerical optimizer that compared model output to predefined neural output, which represented a normal physiological response. Several solutions that restored the neuron function were found. In particular, distinct subtype compositions of the auxiliary proteins Kv channel-interacting proteins 1 and dipeptidyl aminopeptidase-like protein 6 were able to restore changes imposed by the enhanced sodium conductance or suppressed K(A) conductance. Moreover, particular combinations of protein kinese C, calmodulin-dependent protein kinase II, and arachidonic acid were also able to restore these changes as well as the channel pathology found in a patient with temporal lobe epilepsy. The solutions were further analyzed for sensitivity and robustness. We suggest that the optimization procedure can be used not only for neurons, but also for other organs with excitable cells, such as the heart and pancreas where channelopathies are found.

Project description:BackgroundThere is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed.ResultsTo address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)? inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease.ConclusionsWe have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.

Dataset Information

Reversing the Tumor Target: Establishment of a Tumor Trap.

Publications

Reversing the Tumor Target: Establishment of a Tumor Trap.

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