Hypoxia-Dependent Modification of Collagen Networks Promotes Sarcoma Metastasis

Abstract

Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF1α or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSLKrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient tumors, and analysis of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Pharmacological inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

“…[36][37][38] Additionally, multiple growth factor receptor pathways, e.g., epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and growth factor receptor pathway, were also found to be overrepresented. With angiogenesis being among the enriched processes, the vascular endothelial growth factor receptor (VEGFR) pathway likewise indirectly plays a role in the HLA ligand-dependent functional description of RCC.…”

“…20,21,[30][31][32][33][34][35] Furthermore, a vast array of new TAAs with corresponding peptides from HLA class I and II were discovered (Table 3). These included LOX and PLOD2, with high potential in engaging metastasis, [36][37][38] GRB2, ITPR3, and BCAR1, all of which are part of the EGFR pathway 39 and other growth factor receptor pathways, plus ENPEP, NRP2, TGFBI, THBS1, and THBS2, which are essential for angiogenesis. 40 It is notable that 16 out of 24 peptides listed in Table 3 were only found in one tissue sample each.…”

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

“…LOX is induced by HIF-1, cross-links collagens, and facilitates tumor metastasis (7,22,23). Hypoxia affects modification of collagens and metastasis of sarcomas (24). miR-199a also targets IKKβ (25).…”

Intratumoral oxygen gradients mediate sarcoma cell invasion

“…In previous studies, we found that deposition of immature collagen networks facilitated tumor cell metastasis to the lung in an HIF-1α-dependent manner (15). We also demonstrated that the HIF-1α regulated sarcoma metastasis through up-regulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD2), and the resulting increase in lysine hydroxylation of collagen molecules (15).…”

“…We also demonstrated that the HIF-1α regulated sarcoma metastasis through up-regulation of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD2), and the resulting increase in lysine hydroxylation of collagen molecules (15). We have shown that PLOD2 expression promotes metastasis in a hypoxia-and HIF-1α-dependent manner…”