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Development of arterial blood supply in experimental liver metastases.

ABSTRACT: In this study, we present a mechanism for the development of arterial blood supply in experimental liver metastases. To analyze the arterialization process of experimental liver metastases, we elucidated a few key questions regarding the blood supply of hepatic lobules in mice. The microvasculature of the mouse liver is characterized by numerous arterioportal anastomoses and arterial terminations at the base of the lobules. These terminations supply one hepatic microcirculatory subunit per lobule, which we call an arterial hepatic microcirculatory subunit (aHMS). The process of arterialization can be divided into the following steps: 1) distortion of the aHMS by metastasis; 2) initial fusion of the sinusoids of the aHMS at the tumor parenchyma interface; 3) fusion of the sinusoids located at the base of the aHMSs, which leads to the disruption of the vascular sphincter (burst pipe); 4) incorporation of the dilated artery and the fused sinusoids into the tumor; and 5) further development of the tumor vasculature (arterial tree) by proliferation, remodeling, and continuous incorporation of fused sinusoids at the tumor-parenchyma interface. This process leads to the inevitable arterialization of liver metastases above the 2000- to 2500-mum size, regardless of the origin and growth pattern of the tumor.

SUBMITTER: Dezso K

PROVIDER: S-EPMC2716978 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Development of arterial blood supply in experimental liver metastases.

Dezso Katalin K Bugyik Edina E Papp Veronika V László Viktória V Döme Balázs B Tóvári József J Tímár József J Nagy Péter P Paku Sándor S

The American journal of pathology 20090702 2

In this study, we present a mechanism for the development of arterial blood supply in experimental liver metastases. To analyze the arterialization process of experimental liver metastases, we elucidated a few key questions regarding the blood supply of hepatic lobules in mice. The microvasculature of the mouse liver is characterized by numerous arterioportal anastomoses and arterial terminations at the base of the lobules. These terminations supply one hepatic microcirculatory subunit per lobul ...[more]

PMID: 19574433

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Project description:BackgroundMitomycin-C is an older drug which has a synergistic mechanism of action with irinotecan. This study evaluated the outcomes of selective intra-arterial mitomycin-C infusions in combination with bi-weekly systemic irinotecan for treatment of liver-dominant metastatic colorectal cancer (CRC) which progressed after hepatic arterial infusion (HAI) pump chemotherapy with floxuridine and at least two lines of systemic chemotherapy.MethodsAn IRB-approved retrospective review of patients receiving at least two sessions of selective monthly mitomycin-C infusions in interventional radiology (IR) was performed. Anatomic and metabolic imaging was initially obtained at 4 weeks after the second infusion, and every 2-3 months thereafter. Response was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and European Organization for Research and Treatment of Cancer (EORTC) criteria. Patient, disease and procedural parameters were recorded. Progression-free survival (PFS), liver progression-free survival (LPFS) and overall survival (OS) were assessed with Kaplan Meier methodology.ResultsFrom January 2019 to April 2023, 46 patients underwent a total of 190 selective infusions (range 2-10; median 4). Twenty-three/46 (50%) patients had KRAS mutations and 35/46 (76.1%) had extrahepatic disease at the time of the first infusion. On initial follow-up, liver disease control was observed in 38/46 using RECIST 1.1 (82.6%; partial response 13%, stable disease 69.6%) and 26/31 using EORTC criteria (83.9%; complete response 6.5%, partial response 48.4%, stable disease 29%). Median PFS, LPFS and OS were 4.1 [95% confidence interval (CI): 3.2-4.9], 5.5 (95% CI: 2.5-8.4) and 9.6 (95% CI: 8.2-11.1) months respectively. The infusions were discontinued in 26 (56.5%) patients due to disease progression. Eighteen patients (39.1%) discontinued the infusion protocol due to toxicities/complications, including hepatic/biliary toxicity (26.1%), hepatic arterial thrombosis (15.2%) and/or pulmonary toxicity (8.7%).ConclusionsIn this heavily pretreated population, addition of intra-arterial mitomycin-C was associated with initial liver disease control rates exceeding 80%. Toxicities were observed, particularly in patients with prolonged disease control who received ≥4 infusions.

Project description:Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell-cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease.NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.

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Development of arterial blood supply in experimental liver metastases.

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Development of arterial blood supply in experimental liver metastases.

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