Abstract
BackgroundBreast cancer cells invading the connective tissues outside the mammary lobule or duct immerse in a reservoir of extracellular matrix (ECM) that is structurally and biochemically distinct from that of their site of origin. The ECM is a spatial network of matrix proteins, which not only provide physical support but also serve as bioactive ligands to the cells. It becomes evident that the dimensional, mechanical, structural, and biochemical properties of ECM are all essential mediators of many cellular functions. To better understand breast cancer development and cancer cell biology in native tissue environment, various tissue-mimicking culture models such as hydrogel have been developed. Collagen I (Col I) and Matrigel are the most common hydrogels used in cancer research and have opened opportunities for addressing biological questions beyond the two-dimensional (2D) cell cultures. Yet, it remains unclear whether these broadly used hydrogels can recapitulate the environmental properties of tissue ECM, and whether breast cancer cells grown on CoI I or Matrigel display similar phenotypes as they would on their native ECM.MethodsWe investigated mammary epithelial cell phenotypes and metabolic profiles on animal breast ECM-derived tissue matrix gel (TMG), Col I, and Matrigel. Atomic force microscopy (AFM), fluorescence microscopy, acini formation assay, differentiation experiments, spatial migration/invasion assays, proliferation assay, and nuclear magnetic resonance (NMR) spectroscopy were used to examine biological phenotypes and metabolic changes. Student’s t test was applied for statistical analyses.ResultsOur data showed that under a similar physiological stiffness, the three types of hydrogels exhibited distinct microstructures. Breast cancer cells grown on TMG displayed quite different morphologies, surface receptor expression, differentiation status, migration and invasion, and metabolic profiles compared to those cultured on Col I and Matrigel. Depleting lactate produced by glycolytic metabolism of cancer cells abolished the cell proliferation promoted by the non-tissue-specific hydrogel.ConclusionThe full ECM protein-based hydrogel system may serve as a biologically relevant model system to study tissue- and disease-specific pathological questions. This work provides insights into tissue matrix regulation of cancer cell biomarker expression and identification of novel therapeutic targets for the treatment of human cancers based on tissue-specific disease modeling.
Highlights
Breast cancer cells invading the connective tissues outside the mammary lobule or duct immerse in a reservoir of extracellular matrix (ECM) that is structurally and biochemically distinct from that of their site of origin
The mechanical and structural properties of the biogels with native tissue stiffness The stiffness of a hydrogel is a critical factor for cell adhesion [46], spreading [47], proliferation [48, 49], migration [46, 50], invasion [51, 52], differentiation [53], and other biological activities such as neodeposition of matrix proteins [54], interaction with surrounding matrix or cells [55], and expression of gene products [56]
It is important to keep the stiffness of hydrogel in the same range of the corresponding tissues to be mimicked when studying the biology of the cells living in those tissues
Summary
Breast cancer cells invading the connective tissues outside the mammary lobule or duct immerse in a reservoir of extracellular matrix (ECM) that is structurally and biochemically distinct from that of their site of origin. Collagen I (Col I) and Matrigel are the most common hydrogels used in cancer research and have opened opportunities for addressing biological questions beyond the two-dimensional (2D) cell cultures It remains unclear whether these broadly used hydrogels can recapitulate the environmental properties of tissue ECM, and whether breast cancer cells grown on CoI I or Matrigel display similar phenotypes as they would on their native ECM. It was shown that normalizing tumor ECM environment was able to “revert” cancer cell neoplastic phenotype [15] and limit tumor growth and dissemination [16], highlighting the essential role of ECM physicochemical properties on cancer development These ECM-guided cell biological changes suggest potential therapeutic approaches that target ECM rather than cancer cells for treatment or that treatments can be ineffective if, for example, a dense ECM or binding with the ECM limits drug availability [10, 17, 18]. It is important to study cancer cell biology and regulatory mechanisms in tissue-mimicking microenvironments, which are able to facilitate unveiling the nature of carcinogenic processes when it comes to cancer cell adhesion, proliferation, migration, invasion, metastasis, and drug treatment in native tissue space [19,20,21]
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