Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia

Abstract

The liver is a highly vascularized organ which frequently hosts metastases in patients with colorectal adenocarcinomas. The hypothesis of this study is that the hypoxic drive of angiogenesis might be minimal or absent in those growing liver metastases which are capable of preserving the stromal structure, including the numerous sinusoidal blood vessels. Representative paraffin sections of liver metastases from 26 patients with colorectal adenocarcinoma were investigated. Three different growth patterns were found. In the desmoplastic and in the pushing growth patterns (42% and 46% of all metastases, respectively), the architecture of the liver parenchyma was not preserved. In the replacement growth pattern (12% of all cases), the reticulin pattern of the liver parenchyma was conserved within the metastases at the tumour-liver parenchyma interface. The endothelial cells of the blood vessels near the interface in the metastases of the replacement type did not express CD34, nor were they surrounded by alpha-smooth muscle actin-positive mural cells. In the desmoplastic and in the pushing growth patterns, 23% and 52% of all blood vessels in this area were covered by pericytes. The fraction of proliferating endothelial cells was low in the metastases with a desmoplastic or a replacement growth pattern (about 3%), compared with metastases with a pushing growth pattern (11%). Tumour cell apoptosis was highest in the pushing-type metastases and was inversely correlated with microvessel density in liver metastases. The ratio of the proliferating tumour cell fraction and the proliferating endothelial cell fraction, roughly representing the degree of angiogenesis-dependent growth, was three- to four-fold higher in the replacement-type metastases compared with the other metastases. In summary, the present study has demonstrated that liver metastases are a heterogeneous group, with different growth patterns which predict the fraction of immature blood vessels, the fraction of proliferating endothelial cells, and the fraction of apoptotic tumour cells. The replacement growth pattern expands with minimal angiogenesis by co-opting the stroma with the sinusoidal blood vessels of the liver.

Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions

“…4e). Analysis of human cancers reveals vessel co-option in glioblastoma [182, 183], adenocarcinoma of the lung [184, 185] cutaneous melanoma [186], lung metastases of breast and renal cancer [187–189], liver metastases of colorectal and breast cancer [190, 191] and brain metastases of lung and breast cancer [192]. …”

Absence of Smooth Muscle Actin-Positive Pericyte Coverage of Tumor Vessels Correlates with Hematogenous Metastasis and Prognosis of Colorectal Cancer Patients

“…In other words, this observation indicated that tumor vessels in the high MVD tumors consisted of a higher percentage of mature tumor vessels than those in the low MVD tumors. On the other hand, Vermeulen et al [16] demonstrated that in liver metastases from colorectal cancers, the fraction of immature microvessels correlated strongly with the MVD. Kakolyris et al [17, 18] also reported a significant association between a high vascular maturation index and a low microvessel score in non-small-cell lung carcinomas.…”

Relative microvessel area of the primary tumour, and not lymph node status, predicts the presence of bone marrow micrometastases detected by reverse transcriptase polymerase chain reaction in patients with clinically non-metastatic breast cancer

“…The concept of dependence on vascularisation of growth, invasion and metastasis of malignant tumours has been challenged by the description of angiogenesis-independent mechanisms [7-10]. Nevertheless, the growth of most primary tumours needs angiogenesis.…”