Figure 2.

Growth-induced solid stress (GISS), the hypoxia-fibrosis cycle and their contribution to chemoresistance. Continuous PSC activation results in excessive ECM deposition, particularly of tensile-resistant fibrillar collagen as well as compression-resistant hyaluronan. This eventually leads to prominent fibrosis which, along with deformation caused by the number of proliferating stromal cells and cancer cells, results in GISS. Consequently, this reduces the caliber of intratumoral lymphatics and blood vessels. The former leads to increased IFP, which can impair drug perfusion, while the latter reduces blood flow, consequently leading to intrastromal and intratumoral hypoxia. This loops back onto PSCs, driving their activation and hence generating more fibrosis, which creates a hypoxia–fibrosis cycle. The cycle indirectly contributes to chemoresistance by impairing drug delivery to cancer cells. Moreover, hypoxia is capable of increasing the genetic instability and EMT of pancreatic cancer cells, directly fuelling their chemoresistance. EMT, epithelial-mesenchymal transition.