Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis.

Colin E Evans,Love Von Euler,Pär-Ola Bendahl,Petros A Tyrakis,Mattias Belting,Cristina Branco,Helene Rundqvist,Xiao Lu,Alice Prodger,Saria Chan,Randall S Johnson,Asis Palazon,Jingwei Sim

doi:10.1242/bio.024653

Abstract

ABSTRACTThrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2α in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.

Highlights

There is extensive evidence that cancer is a thrombotic disease (Blom et al, 2005; Douketis et al, 2009; Sorensen et al, 2012)
Microbead-induced pulmonary microvascular occlusion induces acute microthrombosis During tumorigenesis, microthrombi can arise in a number of ways, such as from microvascular occlusion by tumour cell aggregates, or fibrin formation as a result of tumour-increased clotting mechanisms (Varki, 2007)
To investigate the relationships between thrombosis, hypoxic response, and metastatic success, we developed a method for modelling ischemic/thrombotic events, one that removed the biological component of the event and its inherent variability

Summary

Introduction

There is extensive evidence that cancer is a thrombotic disease (Blom et al, 2005; Douketis et al, 2009; Sorensen et al, 2012). Significant levels of thrombosis accompany many cancers, notably lung cancer, and cancer treatments such as cytotoxic chemotherapy Thromboembolism is a common cause of death in cancer patients, and both thrombosis and thromboembolism are independent indicators of this condition (Douketis et al, 2009; Sorensen et al, 2012); this association is substantiated by evidence that that anti-coagulants protect against pulmonary metastasis, while thrombotic agents have the opposite effect (Belting, 2014; Langer et al, 2006; Varki, 2007; Wenzel et al, 2010). There is, a lack of experimental models that facilitate elucidation of the mechanisms by which microvascular occlusion and thrombosis promote metastasis

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