In this work, we verified how hyperthermia at different temperature doses (43 °C or 47 °C for 1 h) affects (1) the paracrine (pro-angiogenic) mediator secretion, intracellular HIF-1α accumulation and the ERK phosphorylation of pancreatic adenocarcinoma cells, and (2) sprouting angiogenesis in endothelial spheroids with dependence on the post-treatment oxygen environment and the cell-to-cell contact status of the pancreatic tumor cells (cell monolayers (2D) or spheroids (3D)). Here, HIF1A is linked to pancreatic adenocarcinoma.