Poor perfusion of the microvasculature in peritoneal metastases of ovarian cancer

Abstract

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment. Keywords Microvasculature • Microcirculation • EOC • Peritoneal carcinomatosa • Incident dark field imaging Abbreviations AVI Audio video interleave CD31 Cluster of differentiation 31

3D imaging for driving cancer discovery

“…Combined with advances in optical clearing, it has been instrumental in revealing the full vasculature network of organs, such as the murine brain (Todorov et al , 2020). Moreover, it has been applied to entire tumours, uniquely revealing their chaotic and immature angioarchitecture and identifying tumour areas with poorly‐perfused microvasculature (Dobosz et al , 2014; Kastelein et al , 2020). Next to providing a cause to hypoxia, a well‐recognized tumour feature that often leads to an invasive phenotype of cancer, these findings thereby also explain varying responses to systemic treatment that have been linked to perfusion constraints (Mendler et al , 2016; Viallard et al , 2020).…”

ASO Author Reflections: Challenges of Circulating Tumor DNA in the Management of Gastrointestinal Peritoneal Carcinomatosis

“…Specifically, the physical separation of the peritoneal cavity and systemic circulation by the blood-peritoneal barrier and the poor vascularization of peritoneal metastasis result in decreased access of ctDNA to systemic circulation. 7 In patients with PC, the common indications for ctDNA testing to detect actionable genomic alterations and the evaluation of treatment responses should be used and interpreted with caution. Although, molecular residual disease was beyond the scope of our study, it is reasonable to extrapolate, both based on the findings from our study and others, that a negative ctDNA testing to detect molecular residual disease in tumors with increased predilection for PC should be interpreted with high-degree of suspicion because they may represent a false-negative result.…”

“…Specifically, the physical separation of the peritoneal cavity and systemic circulation by the blood-peritoneal barrier and the poor vascularization of peritoneal metastasis result in decreased access of ctDNA to systemic circulation. 7 …”

A panoramic view of the phenotypic landscape of healthy and tumor tissues

“…Combined with advances in optical clearing, it has been instrumental in revealing the full vasculature network of organs, such as the murine brain (Todorov et al, 2020). Moreover, it has been applied to entire tumours, uniquely revealing their chaotic and immature angioarchitecture and identifying tumour areas with poorly-perfused microvasculature (Dobosz et al, 2014; Kastelein et al, 2020).…”

“…It thereby allows for rapid imaging of very large, even centimetre-scale, specimens, such as entire mice and full human organs, yet at the expense of some resolution. Light sheet imaging has been widely applied to capture the macroscopic properties of cancer, including blood and lymph vasculature(Brown et al, 2018;Kastelein et al, 2020) and whole-body tumour dissemination(Kubota et al, 2017;Pan et al, 2019). In contrast, confocal or two-photon microscopes use high NA objectives to achieve higher resolution and magnification, yet at the sacrifice of some working depth and require lengthier imaging times, thereby more susceptible to photobleaching.…”