Petiveria alliacea and Caesalpinia spinosa extracts reduce the generation of cancer-associated fibroblasts in a 3D platform representative of the tumor microenvironment

Background: The tumor microenvironment (TME) is a complex network of cellular and acellular participants, each of which contributes to ensuring tumor growth. Cancer-associated fibroblasts (CAFs) represent a key TME population that actively participates in stromal remodeling and metabolic coupling with tumors, significantly favoring both the process of carcinogenesis and the establishment of metastasis. Therefore, developing therapies that target CAFs constitute valuable therapeutic alternatives. However, efficiently modeling the generation of CAFs in the tumor microenvironment is challenging. Methods: We constructed a 3D structure of the tumor microenvironment (TME), which we refer to as “TME spheroids”. These spheroids are composed of 4T1 murine breast cancer cells and 3T3 murine fibroblasts, allowing us to mimic the development of a cancer-associated fibroblast (CAF) phenotype. This novel 3D model serves as a platform for evaluating the impact of two natural extracts on TME interactions and their ability to impede tumor progression. Results: Using the TME-spheroid model, we tested the effects of two extracts on CAF generation: Anamu-SC obtained from Petiveria alliacea and P2Et from Caesalpinia spinosa. Both extracts disrupted the interaction between tumor cells and fibroblasts, reducing the ability of CAFs to support tumor growth and spread. Conclusions: We found that the two extracts interfere with circuits that drive tumor-fibroblast crosstalk, attenuating the phenotype and functional activities associated with CAFs in this TME model.