Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer

Abstract

Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein (CLEC)14A as a potential downstream target of ACVRL1. Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer.

Key Vitamin D Target Genes with Functions in the Immune System

“…The CEBPB gene has already been described as a vitamin D target in myeloid leukemia cells [72]. ACVRL1 is a transmembrane protein of the transforming growth factor beta superfamily, which mediates the bone morphogenetic protein (BMP) 9-and BMP10-induced signaling that orchestrates the development of blood vessels [73]. This relates to the control of monocyte to macrophage differentiation [74].…”

An evaluation of the tumour endothelial marker CLEC14A as a therapeutic target in solid tumours

“…Earlier studies of CLEC14A expression reported that it is upregulated in many solid tumours including those of the ovary, prostate, breast, liver, bladder, kidney and lung [1,2]. This may partly reflect the reduced flow rate often present within tumour vasculature [3]; however, recent studies indicate that, in cancer, CLEC14A expression may be regulated by other pathways [4]. Poor tumour growth in CLEC14A (−/−) mice compared to wild type mice confirmed that CLEC14A promotes tumour growth [5].…”

Matrine promotes apoptosis in SW480 colorectal cancer cells via elevating MIEF1‐related mitochondrial division in a manner dependent on LATS2‐Hippo pathway

“…Colorectal cancer (CRC) accounts for 8.5% of cancer‐related deaths and effective approaches to control CRC include oxaliplatin (OXP), 5‐fluorouracil (5‐FU), and irinotecan (CPT‐11; Bocci et al, ; Chrifi et al, ). Unfortunately, a considerable proportion of CRC patients develop acquired resistance, and thus the overall survival rate of CRC patients is 12–18 months (Abukar et al, ; Botker et al, ).…”