Vascular niches: endothelial cells as tissue- and site-specific multifunctional team players in health and disease.

The cardiovascular system is a circulatory system that transports the blood and reaches out to almost every site of the body. Endothelial cells (EC) as the innermost cell layer of blood vessels constitute a huge interface between the blood and nearly all other tissues and cells. Although blood vessels and their EC were considered as rather inert and passive conduits early in the history of vascular discoveries, progress in vascular research now suggests that EC are actively involved in a plethora of physiological or pathophysiological processes. Endothelial heterogeneity and the concept of vascular niches are in the spotlight of current research in vascular biology. Endothelial heterogeneity comprises morphologic, molecular and functional features. It allows EC to adapt to the organ- and site-specific requirements exhibited by different segments of the vascular tree. In organ-specific vascular niches, EC mutually interact with neighboring cells. EC-derived cytokines, called angiokines, acting in a paracrine (angiocrine) fashion have been shown to be decisively involved in various biological processes ranging from stem cell maintenance to organ regeneration as well as cancer progression and metastasis. In summary, EC should always be considered as teammates in the maintenance and regulation of complex multicellular network interactions in health and disease.

The metastatic cycle: metastatic niches and cancer cell dissemination.

The concept of a unidirectional cascade of metastatic events has been replaced in recent years by the metastatic cycle - the concept of a dynamic feed forward cycle of metastatic niches that evolve upon reciprocal interactions with the primary tumor and disseminating cancer cells. Primary tumors interact with pre-metastatic sites preparing organ-specific pre-metastatic niches. Metastasis-initiating cells home to and succumb to interactions with developing organ-specific metastatic niches, and secondary recirculating cancer cells interact back with the primary. Metastatic tropism as well as metastatic disease progression are a result of this feed forward cycle of dynamic, reciprocal interactions of cancer cells with their diverse metastatic niches. A better understanding of the multifaceted contributions of the organ-specific metastatic niches and their complex changes on cancer cell dissemination and of the mutual effects of the cellular and molecular mechanisms involved will open new avenues to better therapies for hitherto intractable progressive disease states of cancer patients and for adjuvant treatment options preventing relapses in tumor-free patients.

Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC. METHODS: The murine inducible albumin-SV40-large T-antigen model and two tissue microarrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b. RESULTS: LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 µm in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63-95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion. CONCLUSIONS: In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.