The tumori microenvironment functionally links malignant cells with surrounding cellular and acellular elements to promote disease progression and therapy resistance. At the time of diagnosis, the majority of ovarian cancer patients have metastatic disease, and their survival rates have not changed over the past decades. This slow progress in improving survival outcomes is caused by the ‘one-size-fits-all’ therapeutic approach and, most importantly, the lack of clinically relevant experimental models that mimic the progression of the human disease to find better therapeutic options. Thus, the objective of this study was to develop a 3D bioengineered mimic of the tumori microenvironment of ovarian cancer.
Ovarian cancer spheroids, which form within hydrogels, were assembled with mesothelial cell-layered scaffolds, which were produced by melt electrospinning, to build a 3D co-culture model. These 3D constructs were investigated for their proliferative and transcriptomic features and for their tumor-promoting role in an intra-peritoneal animal model. Significant factors were clinically validated using patient-derived cells, immunohistochemistry of patient-derived tissues and correlated with overall and progression-free survival.
Spheroid and tumor growth were enhanced upon 3D co-culture compared to 3D mono-culture. Proliferation of patient-derived cells was stimulated upon 3D co-culture. The cyclooxygenase-2 network and its extracellular inter-actors were upregulated upon 3D co-culture, with a further increase in the presence of kallikrein-related peptidases, an emerging ovarian cancer biomarker family. Cyclooxygenase-2 expression correlated with poor survival of ovarian cancer patients. In agreement with published studies, these identified factors are linked to critical steps in cancer progression and the advanced stage of the disease.
Recreating autocrine and paracrine regulators of the tumori microenvironment is an essential requisite for a clinically relevant disease model; thus, the engineering of 3D constructs that allow the co-culture of cancer spheroids and mesothelial cells represents a conceptual approach to mimic the molecular composition of the microenvironment of ovarian cancer.