Impact of acute, short-term, hypoxia on the development and progression of colorectal cancer liver metastases in the context of partial hepatectomy

Details

Supervisors

Dili, Alexandra ; Leclercq, Isabelle

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Introduction: Surgical resection is important in the curative treatment of liver tumors. However, the risk of developing a postoperative liver failure know as post-hepatectomy liver failure, limits the number of pa-tients eligible for surgery. In our laboratory, an extended hepatic resection model has been developed in rodents. We have demon-strated that acute and early hypoxia after hepatectomy exerts a beneficial effect on the remaining liver. It initiates early angiogenesis, improves vascular architecture, limits hepatocyte proliferation and maintains the epithelial signature of hepatocytes. A short and well-controlled hypoxic stimulus, therefore, promotes liver regeneration. Hepatic metastases in the context of colorectal neoplasia are very common. Hepatic resection is the only curative treatment, improving overall and recurrence-free survival. A tumor mass consists of tumor cells proliferating chaotically while losing their initial epithelial characteristics, a phenomenon called “epithelial-mesenchymal transition” (EMT). Simultaneously, as a tumor grows, a hypoxic environment develops, ac-companied by abnormal angiogenesis: tumor blood vessels from a disorganized network with disrupted endothelial junctions and increased permeability, promoting metastatic spread. Chaotic proliferation, EMT and intra tumoral hypoxia-angiogenesis are closely linked to the malignant and metastatic potential of neo-plasms. Aim: This study aim to investigate the impact of a brief hypoxic stimulus on tumor growth. Since this stimu-lus is beneficial in reducing the risk of postoperative liver failure, our study currently focuses on tumor growth, angiogenesis and intra tumoral EMT in a hypoxic environment. Methods: We use an animal model of colorectal-origin metastases (MC38) implanted in C57BL/6 mice. We study the effects of short-term hypoxia on tumor growth, proliferation and vascularization. Additionally, we examine the impact of hepatic resection under normoxic and hypoxic conditions. Results: Our results indicate that, in our experimental model, short-term hypoxia does not affect tumor proliferation, vascularization, EMT status, or activation of hypoxia-related transcription factors (HIF1-α), regardless of the presence or absence of hepatic resection. Conclusion: Our findings suggest that brief, titrated hypoxia does not influence tumor morphology after hepatic resection. Hypoxia, which is beneficial for liver regeneration, could thus be a safe therapeutic ap-proach in cases of postoperative failure. However, it is important to note that hepatectomy might promote tumor growth, warranting careful consideration.