Vasculogenic mimicry in malignant mesothelioma and its treatment potential

Author: Ash Hocking

  • Thesis download: available for open access on 16 Jan 2022.

Hocking, Ash, 2019 Vasculogenic mimicry in malignant mesothelioma and its treatment potential, Flinders University, College of Medicine and Public Health

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Abstract

Malignant pleural mesothelioma is a devastating cancer of the mesothelial cells that line the pleural cavity. Despite considerable efforts, little progress has been made towards improving patient survival and quality of life. Anti-angiogenic therapies have the potential to improve outcomes for patients with mesothelioma but, thus far, have only marginally improved patient survival. This may be, in part, due to compensation from alternative mechanisms of tumour vascularisation such as vasculogenic mimicry. Vasculogenic mimicry is a unique capability that some tumour cells possess, which allows them to form vascular channels, void of a vascular-derived endothelial layer. Vasculogenic mimicry has been linked to metastasis and poor prognosis in numerous solid tumours but has not been characterised in malignant mesothelioma. We hypothesised that the relative resistance of mesothelioma to anti-angiogenic therapies might be related to the ability of tumour cells to exhibit vasculogenic mimicry.

To test this hypothesis, we investigated whether mesothelioma cells could mimic the pattern of endothelial cells when seeded onto a basement membrane in vitro. We found that 87% of primary mesothelioma cells formed 3-dimensional tubular networks on a basement membrane, in a similar manner to endothelial cells. Additionally, we looked for immunohistological evidence of vasculogenic mimicry in NCI-H226 derived tumours and mesothelioma biopsies. We identified tumour derived microvascular structures in archival NCI-H226 tumours that were xenotransplanted into nude mice. Evidence of vasculogenic mimicry was also shown in five of eighteen human mesothelioma biopsy samples. We demonstrated tumour-lined vessels, which showed co-labelling of epithelial- and endothelial-specific markers. Theses data might provide a new insight into the mechanism of intrinsic or adaptive resistance that malignant mesotheliomas display towards anti-angiogenic therapy.

Several separate studies have demonstrated that cancer stem cells can differentiate into endothelial-like cells and contribute to vasculogenic mimicry channel formation. A stem cell factor-based lentiviral reporter system was utilised to explore the role of mesothelioma cancer stem cell in vasculogenic mimicry in vitro. We showed that cancer stem cells are present in cells undergoing vasculogenic mimicry in vitro, but it is still unclear whether they are obligatory for the process to occur.

Providing adjunct therapy targeting vasculogenic mimicry might help improve survival outcomes for malignant pleural mesothelioma patients. Curcumin, a polyphenol found in the spice turmeric, is an attractive potential anti-cancer therapy as it acts on a wide range of molecular pathways and has relatively low toxicity. Here we showed, for the first time, that curcumin inhibited the ability of mesothelioma cells to exhibit vasculogenic mimicry in vitro at non-cytotoxic concentrations. We also confirmed previous findings that curcumin could inhibit proliferation of mesothelioma in cell lines and our cohort of primary cells.

Difficulties with clinical translation exist as curcumin is poorly absorbed into the circulation via the intestinal mucosa and undergoes rapid biotransformation in the blood. We hypothesise that curcumin could be instilled into the pleural cavity of patients with mesothelioma through tunnelled indwelling pleural catheters to help overcome these pharmacokinetic obstacles. As a part of this body of work, we aimed to evaluate the safety and pharmacokinetics of curcumin when applied directly to the pleural cavity of experimental animals. Two types of curcumin were used: unformulated curcumin; and later, a pharmaceutical-grade liposomal formulated curcumin. Intrapleural delivery of unformulated curcumin in slurry caused a mild benign reactive mesothelial hyperplasia, which was attributed to either the particulate matter of the slurry or the bioactive curcumin compound. Intrapleural delivery of liposomal curcumin was found to be safe when applied to the pleural cavity, at concentrations that caused red blood cell abnormalities when administered intravenously. It is envisaged that curcumin may be used as an adjunct therapy or could be used as a less toxic treatment in patients who are unable to tolerate or are unwilling to undergo standard chemotherapy. Additionally, intrapleural liposomal curcumin could be used alone to treat patients with pre-invasive mesothelioma lesions

Keywords: Mesothelioma, vasculogenic mimicry

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2019
School: College of Medicine and Public Health
Supervisor: Associate Professor Sonja Klebe