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 8

Quantification of vaso-occlusion and residual viable tumor in sections of established LLC obtained on day 20 from in SSKI and AAKI mice after treatment with tumor SR (10 Gy) on day 12 followed by CA-4 on days 13, 15, and 18.

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Quantification of vaso-occlusion and residual viable tumor in sections o...
(A) Vessel closure in SSKI mice treated with radiation and CA-4 exceeded that of similarly treated AAKI mice (**P = 0.003) and all other controls (*P ≤ 0.003, n = 4–6). (B) Residual viable LLC in sections obtained on day 20 from SSKI mice treated with sublethal radiation (10 Gy) on day 12 followed by CA-4 on days 12, 15, and 18 was significantly diminished relative to similarly treated AAKI mice (**P = 0.005) and all other controls (*P < 0.01, 2-tailed Student’s t test; n = 3).