Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression
Chiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, David S. Terman
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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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 9

Chain of events leading to massive SSRBC-mediated tumor vaso-occlusion and infarction in tumor microvessels conditioned for tumor vascular injury by CA-4 and tumor SR is shown.

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Chain of events leading to massive SSRBC-mediated tumor vaso-occlusion a...
Untreated LLC shows a modest degree of focal tumor hypoxia. Introduction of sublethal radiation initiates tumor endothelial mitotic-based and oxidant-mediated injury followed within 24 hours by CA-4, which induces endothelial tubulin depolymerization and cytoskeletal injury. Subsequent addition of SSRBCs and their contact with the tumor endothelium induces further oxidant-mediated damage. The combined effect results in severe tumor hypoxia and vascular injury resulting in blood flow stagnation. Under these conditions, HbS deoxygenates and polymerizes, and the SSRBCs assume the sickle morphology forming aggregates that adhere to the tumor vessel wall. A surge of SSRBC-mediated tumor vaso-occlusion ensues with disseminated mononuclear cell infiltration and infarction. The scale of the tumor infarction engulfs the entire tumor including treatment-resistant hypoxic niches and the tumor rim. The comprehensive tumor eradication leads to tumor regression and a major histopathological treatment effect.