Fibroblasts Influence Survival and Therapeutic Response in a 3D Co-Culture Model

Abstract

In recent years, evidence has indicated that the tumor microenvironment (TME) plays a significant role in tumor progression. Fibroblasts represent an abundant cell population in the TME and produce several growth factors and cytokines. Fibroblasts generate a suitable niche for tumor cell survival and metastasis under the influence of interactions between fibroblasts and tumor cells. Investigating these interactions requires suitable experimental systems to understand the cross-talk involved. Most in vitro experimental systems use 2D cell culture and trans-well assays to study these interactions even though these paradigms poorly represent the tumor, in which direct cell-cell contacts in 3D spaces naturally occur. Investigating these interactions in vivo is of limited value due to problems regarding the challenges caused by the species-specificity of many molecules. Thus, it is essential to use in vitro models in which human fibroblasts are co-cultured with tumor cells to understand their interactions. Here, we developed a 3D co-culture model that enables direct cell-cell contacts between pancreatic, breast and or lung tumor cells and human fibroblasts/ or tumor-associated fibroblasts (TAFs). We found that co-culturing with fibroblasts/TAFs increases the proliferation in of several types of cancer cells. We also observed that co-culture induces differential expression of soluble factors in a cancer type-specific manner. Treatment with blocking antibodies against selected factors or their receptors resulted in the inhibition of cancer cell proliferation in the co-cultures. Using our co-culture model, we further revealed that TAFs can influence the response to therapeutic agents in vitro. We suggest that this model can be reliably used as a tool to investigate the interactions between a tumor and the TME.

Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression

“…Consistent with this, in a 3D co-culture model, the co-culture of MRC5 fibroblasts and cancer cell lines increased the survival of several types of cancer cells [1]. In lung cancer, however, only 2 of the 7 cell lines tested exhibited increased survival when co-cultured with MRC5 cells for 5 days, and no increased survival was observed in A549 cells [1].…”

3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs

“…This improved proliferation of the cells was attributed to the increased secretion of epidermal growth factor (EGF), HGF, and IL-6, when cells were maintained in coculture (Majety et al, 2015). This improved proliferation of the cells was attributed to the increased secretion of epidermal growth factor (EGF), HGF, and IL-6, when cells were maintained in coculture (Majety et al, 2015).…”

Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement

“…N. Wang, Albo, & Tuszynski, 2002). Mounting evidence supports that the absence of these components result in a decreased drug resistance, suggesting incorporation of at least some of these factors is necessary to accurately predict drug response (Chitcholtan, Asselin, Parent, Sykes, & Evans, 2013; Gajewski, Schreiber, & Fu, 2013; Loessner et al, 2010; Majety, Pradel, Gies, & Ries, 2015; Pan et al, 2015; Z. Xu et al, 2013).…”