Hyperthermia Influences the Secretion Signature of Tumor Cells and Affects Endothelial Cell Sprouting

• Published in: Biomedicines Vol. 11; no. 8; p. 2256
• Main Authors: Maduabuchi, Wisdom O, Tansi, Felista L, Heller, Regine, Hilger, Ingrid
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2023; MDPI
• Subjects: Adenocarcinoma; Angiogenesis; Angiopoietin; Apoptosis; Cancer therapies; Cell culture; Cell growth; Chemotherapy; Cytotoxicity; Endothelial cells; endothelial cells (EC); Endothelium; Environmental conditions; Extracellular matrix; Extracellular signal-regulated kinase; extracellular signal-regulated kinase (ERK); Fever; Gene expression; Health aspects; Hyperthermia; Hypoxia; Hypoxia-inducible factor 1a; Intracellular; Kinases; Lung cancer; Macrophage colony-stimulating factor; MAP kinase; Pancreatic cancer; pancreatic ductal adenocarcinoma (PDAC); Penicillin; Phosphorylation; Platelet-derived growth factor; Platelet-derived growth factor BB; Secretion; Spheroids; sprouting angiogenesis; Temperature; Tumor cells; Tumors; Vascular endothelial growth factor; vascular endothelial growth factor (VEGF); Germany; United States > US
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11082256

Tumors are a highly heterogeneous mass of tissue showing distinct therapy responses. In particular, the therapeutic outcome of tumor hyperthermia treatments has been inconsistent, presumably due to tumor versus endothelial cell cross-talks related to the treatment temperature and the tumor tissue environment. Here, we investigated the impact of the average or strong hyperthermic treatment (43 °C or 47 °C for 1 h) of the human pancreatic adenocarcinoma cell line (PANC-1 and BxPC-3) on endothelial cells (HUVECs) under post-treatment normoxic or hypoxic conditions. Immediately after the hyperthermia treatment, the distinct repression of secreted pro-angiogenic factors (e.g., VEGF, PDGF-AA, PDGF-BB, M-CSF), intracellular HIF-1α and the enhanced phosphorylation of ERK1/2 in tumor cells were detectable (particularly for strong hyperthermia, 2D cell monolayers). Notably, there was a significant increase in endothelial sprouting when 3D self-organized pancreatic cancer cells were treated with strong hyperthermia and the post-treatment conditions were hypoxic. Interestingly, for the used treatment temperatures, the intracellular HIF-1α accumulation in tumor cells seems to play a role in MAPK/ERK activation and mediator secretion (e.g., VEGF, PDGF-AA, Angiopoietin-2), as shown by inhibition experiments. Taken together, the hyperthermia of pancreatic adenocarcinoma cells in vitro impacts endothelial cells under defined environmental conditions (cell-to-cell contact, oxygen status, treatment temperature), whereby HIF-1α and VEGF secretion play a role in a complex context. Our observations could be exploited for the hyperthermic treatment of pancreatic cancer in the future.