title: 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.
authors.affiliation: Discovery Oncology, Roche Innovation Center Penzberg, Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Meher
authors.initials: M
authors.lastname: Majety
authors.affiliation: Discovery Oncology, Roche Innovation Center Penzberg, Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Leon P
authors.initials: LP
authors.lastname: Pradel
authors.affiliation: Discovery Oncology, Roche Innovation Center Penzberg, Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gies
authors.affiliation: Discovery Oncology, Roche Innovation Center Penzberg, Pharmaceutical Research and Early Development, Penzberg, Germany.
authors.forename: Carola H
authors.initials: CH
authors.lastname: Ries
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D018920:Coculture Techniques / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins