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

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 1

Brightfield and corresponding hemoglobin saturation images of an established Caki-1 tumor before and after CA-4 administration.

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Brightfield and corresponding hemoglobin saturation images of an establi...
(A, D, and G) Pretreatment images show original vascular structure with Hb saturation of less than 10% enveloping 38% of the tumor area. (B, E, and G) Four hours after CA-4 administration, tumor vessels in the tumor exhibit vascular collapse (circle, compare B and A) associated with Hb saturation of less than 10% covering 64% of the tumor area. **P ≤ 0.000002 compared with pretreatment values. (C and F) Forty-eight hours after CA-4 administration, core vessels show oxygenation recovery with Hb saturation less than 10% engulfing 24% of the tumor surface. *P ≤ 0.00005 and ***P ≤ 0.000001 compared with pretreatment and 4-hour posttreatment levels respectively, by 2-tailed Student’s t test. Images were obtained at ×2.5 original magnification with image dimensions of 4.15 × 3.125 mm. The color scale shows percentage Hb saturation values. n = 5 separate readings of Hb saturation less than 10% using ImageJ software to determine percentage tumor area.