Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Abstract

Besides the nervous system, L1 is expressed in many human cancers, including ovarian and endometrial carcinoma, pancreatic ductal adenocarcinoma (PDAC), melanoma and glioblastoma. L1 expression confers motile and invasive properties to tumor cells, supporting cancer growth, metastasis, and chemoresistance and often acting as a marker of poor prognosis (8). L1 has also been detected in the hematopoietic system, in particular in immune cells of myelomonocytic and lymphoid origin (9), and we have previously reported L1-dependent transmigration of dendritic cells across the endothelium (10).An intriguing aspect of L1 biology is its expression in the vascular system: while no or very little L1 is detectable in the vasculature of most normal tissues, its level is markedly increased in the vasing the mechanisms of pathological angiogenesis and to identifying novel cancer vessel-specific markers.L1 (also known as L1CAM or CD171) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is composed of an extracellular portion, containing 6 Ig-like domains and 5 fibronectin type III repeats, followed by a transmembrane region, and a highly conserved cytoplasmic tail (5). L1 was discovered and characterized as a cell-adhesion molecule in the nervous system (6), where it is involved in neurite outgrowth and fasciculation as well as cell adhesion and migration. In addition to homophilic binding, L1 can establish cis-or trans-interactions with different binding partners, such as integrins, CD24, neurocan, neuropilin-1, and other members of the neural cell adhesion family (7).

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

“…Robust angiogenic effects of JAK/STAT signals [7][8][9] and angiostatic effects of SOCS3 5 have been previously described. JAK/STAT signals are normally accompanied by the induction of SOCS, which exerts negative feedback regulation of this pathway.…”

“…[7][8][9] For instance, cell adhesion molecule L1 reportedly participates in an activation of ECs, vascular destabilization, and angiogenic responses because of its ability to upregulate JAK/STAT signals in ECs. 7 Furthermore, ablation of endothelial suppressor of cytokine signaling 3 (SOCS3), an endogenous inhibitor of JAK/STAT signals, reportedly accelerates growth factor-induced angiogenesis and cytokine-induced angiogenesis, thereby aggravating cancer growth and oxygen-induced retinopathy (OIR) in mice. 5 Thus, it is considered that JAK/STAT/SOCS signals play a pivotal role in pathological angiogenesis under the inflammatory conditions.…”

JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study

“…EnMT has been proposed as cellular mechanism to increase the number of lung myofibroblasts from endothelial cells to increase lung fibrosis in animal and human studies 4 19. Recent studies indicate that EnMT can be mediated through the activation of JAK/STAT3 pathway in endothelial cells from different types of cancer 34. Moreover, TGFβ1 activates JAK2 and STAT3 in SSc, and pharmacological or genetic inactivation of JAK2 reduces the skin profibrotic effects of TGFβ1 12.…”

HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis

“…During cardiac fibrosis, bone morphogenetic protein 7 suppresses the EndMT (23). Moreover, cluster of differentiation (CD) 171 regulates the EndMT via JAK-STAT signaling in pancreatic tumors, suggesting that the EndMT is crucial for tumor vasculogenesis (24). Different phenotypes of the TGFb-induced EndMT may be related to the plasticity and heterogeneity of the tumor vasculature (25).…”