Pseudo-hemorrhagic region formation in pancreatic neuroendocrine tumors is a result of blood vessel dilation followed by endothelial cell detachment

Abstract

Aberrant blood vessel formation and hemorrhage may contribute to tumor progression and are potential targets in the treatment of several types of cancer. Pancreatic neuroendocrine tumors (PNETs) are highly vascularized, particularly when they are well-differentiated. However, the process of vascularization and endothelial cell detachment in PNETs is poorly understood. In the present study, 132 PNET clinical samples were examined and a special type of hemorrhagic region was observed in ~30% of the samples regardless of tumor subtype. These hemorrhagic regions were presented as blood-filled caverns with a smooth boundary and were unlined by endothelial cells. Based on the extensive endothelial cell detachment observed in the clinical samples, the formation process of these blood-filled caverns was hypothesized. Blood vessel dilation followed by detachment of endothelial cells from the surrounding tumor tissue was speculated. This was further supported using an INS-1 xenograft insulinoma model. As the formation process was distinct from the typical diffusive hemorrhage, it was named ‘pseudo-hemorrhage’. Furthermore, it was demonstrated that epithelial (E-) cadherin and β-catenin were overexpressed in tumor cells surrounding these pseudo-hemorrhagic regions. Therefore, even though no statistically significant association of pseudo-hemorrhage with clinical features (metastasis or disease recurrence) was identified, the high levels of E-cadherin and β-catenin expression may suggest that a number of features of normal islet cells are retained.

A Rare Presentation of Peliosis Hepatis in a Patient with a Metastatic Neuroendocrine Tumor

“…The presence of a neuroendocrine tumor in this case is unique and raises the possibility of another called "pseudo-hemorrhage," a process previously observed with pancreatic neuroendocrine tumors by which blood vessels dilate, followed by endothelial cell detachment, resulting in lakes or caverns of blood within the parenchyma. In this presentation of PH a similar mechanism might be present [5]. Further study, however, is warranted is to better understand the pathophysiology of PH and its clinical significance.…”

Apatinib inhibits tumor growth and angiogenesis in PNET models

“…1D, E and F). For subcutaneous tumors, although INS-1 xenograft tumors (26) caused severe hypoglycemia, the blood glucose level showed no significant change in INR1G9-tumor-bearing mice (Fig. 1G).…”

“…The INS-1 cell line was from an X-ray-induced rat insulinoma, which expressed high levels of insulin and small amounts of glucagon. The establishment of a subcutaneous tumor model has been proven to be accessible (26). With the symptom of hypoglycemia (Fig.…”

“…For INS-1 tumors, we have demonstrated that a special type of hemorrhagic-like region presents as blood-filled caverns with a smooth boundary and unlined by endothelial cells. This pseudo-hemorrhagic region formation is a result of blood vessel dilation followed by endothelial cell detachment (26). In the present study, we found that inhibition of angiogenesis in INS-1 tumors significantly reduced the areas of pseudo-hemorrhagic regions (Fig.…”

“…Intra-tumoral hemorrhage is common in PNETs. We have previously demonstrated that the pseudo-hemorrhagic region formation in INS-1 tumors is a result of vessel dilation followed by endothelial cell detachment, which is not relevant to tumor malignancy (26). In the present study, we showed that this pseudo-hemorrhagic region formation could be inhibited by anti-angiogenesis treatments.…”