Figure 4.

Ectopic ossification in PMP. The tumor microenvironment is composed of cellular and acellular elements, whose interaction may create a dynamic landscape in which EMP takes place. Cytokines and chemokines initially expressed by tumor cells and then induced in the attracted stromal and immune cells may promote cell plasticity. In the context of PMP, TGF-β/BMP9 secreted by PMP cells and expressed by stromal cells may induce EMT in an autocrine and/or paracrine loop. Tumor cells, after having transitioned into a more mesenchymal state, may differentiate towards an osteoblast-like phenotype. In a similar manner, mesenchymal stromal cells, influenced by the same stimuli, may undergo a transition to osteoblast-like cells. These cells were shown to express osteoblastic markers and are very likely responsible for pathologic formation of extraskeletal bone. TGF-β/BMP9: Transforming growth factor-beta/Bone morphogenetic protein 9; BGLAP: Bone γ-carboxyglutamic acid-containing protein or Osteocalcin; OPN: Osteopontin.