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Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression
Chiao-Wang Sun, … , Tim M. Townes, David S. Terman
Chiao-Wang Sun, … , Tim M. Townes, David S. Terman
Published April 4, 2019
Citation Information: JCI Insight. 2019;4(7):e125535. https://doi.org/10.1172/jci.insight.125535.
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Research Article Hematology Oncology

Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression

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Abstract

Hypoxic tumor niches are chief causes of treatment resistance and tumor recurrence. Sickle erythrocytes’ (SSRBCs’) intrinsic oxygen-sensing functionality empowers them to access such hypoxic niches wherein they form microaggregates that induce focal vessel closure. In search of measures to augment the scale of SSRBC-mediated tumor vaso-occlusion, we turned to the vascular disrupting agent, combretastatin A-4 (CA-4). CA-4 induces selective tumor endothelial injury, blood stasis, and hypoxia but fails to eliminate peripheral tumor foci. In this article, we show that introducing deoxygenated SSRBCs into tumor microvessels treated with CA-4 and sublethal radiation (SR) produces a massive surge of tumor vaso-occlusion and broadly propagated tumor infarctions that engulfs treatment-resistant hypoxic niches and eradicates established lung tumors. Tumor regression was histologically corroborated by significant treatment effect. Treated tumors displayed disseminated microvessels occluded by tightly packed SSRBCs along with widely distributed pimidazole-positive hypoxic tumor cells. Humanized HbS-knockin mice (SSKI) but not HbA-knockin mice (AAKI) showed a similar treatment response underscoring SSRBCs as the paramount tumoricidal effectors. Thus, CA-4-SR–remodeled tumor vessels license SSRBCs to produce an unprecedented surge of tumor vaso-occlusion and infarction that envelops treatment-resistant tumor niches resulting in complete tumor regression. Strategically deployed, these innovative tools constitute a major conceptual advance with compelling translational potential.

Authors

Chiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, David S. Terman

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Figure 4

Ki-67 uptake in sections of LLC in C57BL/6J mice obtained on day 14 after treatment with tumor SR (10 Gy) on day 12 followed by CA-4 plus passive infusion of SSRBC or AARBC on day 13.

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Ki-67 uptake in sections of LLC in C57BL/6J mice obtained on day 14 afte...
(A) Nuclear Ki-67 uptake by LLC cells, an indicator of mitotically active tumor cells, from untreated mice and (B) in mice treated with SSRBC-based triple therapy is shown. (C) Ki-67 uptake in tumor sections after 1 cycle of SSRBC-based triple therapy was diminished relative to that of AARBC-based triple therapy (**P ≤ 0.0001, 2-tailed Student’s t test) and all dual and single treatments (*P ≤ 0.0001, n = 3). Ki-67–immunopositive cells were quantified in tumor sections in 30 separate fields at ×40 original magnification.

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