Collagen reorganization at the tumor-stromal interface facilitates local invasion

By Paolo P. Provenzano, Kevin W. Eliceiri, Jay M. Campbell, David Inman, J. White, P. Keely. BMC Medicine, 2006

1,768 citations recorded by the source corpus.

BackgroundStromal-epithelial interactions are of particular significance in breast tissue as misregulation of these interactions can promote tumorigenesis and invasion. Moreover, collagen-dense breast tissue increases the risk of breast carcinoma, although the relationship between collagen density and tumorigenesis is not well understood. As little is known about epithelial-stromal interactions in vivo, it is necessary to visualize the stroma surrounding normal epithelium and mammary tumors in intact tissues to better understand how matrix organization, density, and composition affect tumor formation and progression.MethodsEpithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture were studied with histology, electron microscopy, and nonlinear optical imaging methodologies. Imaging of the tumor-stromal interface in live tumor tissue ex vivo was performed with multiphoton laser-scanning microscopy (MPLSM) to generate multiphoton excitation (MPE) of endogenous fluorophores and second harmonic generation (SHG) to image stromal collagen.ResultsWe used both laser-scanning multiphoton and second harmonic generation microscopy to determine the organization of specific collagen structures around ducts and tumors in intact, unfixed and unsectioned mammary glands. Local alterations in collagen density were clearly seen, allowing us to obtain three-dimensional information regarding the organization of the mammary stroma, such as radiating collagen fibers that could not have been obtained using classical histological techniques. Moreover, we observed and defined three tumor-associated collagen signatures (TACS) that provide novel markers to locate and characterize tumors. In particular, local cell invasion was found predominantly to be oriented along certain aligned collagen fibers, suggesting that radial alignment of collagen fibers relative to tumors facilitates invasion. Consistent with this observation, primary tumor explants cultured in a randomly organized collagen matrix realigned the collagen fibers, allowing individual tumor cells to migrate out along radially aligned fibers.ConclusionThe presentation of these tumor-associated collagen signatures allowed us to identify pre-palpable tumors and see cells at the tumor-stromal boundary invading into the stroma along radially aligned collagen fibers. As such, TACS should provide indications that a tumor is, or could become, invasive, and may serve as part of a strategy to help identify and characterize breast tumors in animal and human tissues.

Subfields: Biophysics, Cell Biology, Immunology and Allergy

View Paper: https://www.semanticscholar.org/paper/1292d59dd3c4ef10136036003a186e43222bc4e3

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Citations in the corpus

Role of Extracellular Matrix in Development and Cancer Progression (2018, background): “Indeed, changes in the deposition or degradation of collagen can lead to the loss of ECM homeostasis [130,131].”
Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells (2007, background): “Furthermore, similar tracks and extensive collagen remodelling is a common feature of invasive tumour margins and has been previously reporte”
Physical traits of cancer (2020, background): “Studies of 3D matrix architecture, mainly focused on collagen, show that collagen organization can be a prognostic biomarker (119) and that certain arrangements facilitate cancer cell migration, proliferation, and actomyosin contractility (120, 121).”
Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited (2009, background): “…of the tumor cell invasion program proceed through collagen-rich areas whose penetration would appear to be more consistent with the slower advance of proteolytically active neoplastic cell populations (Li et al., 2000; Curino et al., 2005; Provenzano et al., 2006, 2008a; Kedrin et al., 2008).”
Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer (2011, neutral): “…cells at the invasive front of the tumor is a classic example of malignant transformation (Levental et al., 2009) and metastatic dissemination (Provenzano et al., 2006), and transformed mammary epithelial cells are often found on bundles of linear collagen fibers adjacent to blood vessels…”
Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression (2015, background): “Rather than the relaxed, non-oriented fibrils found in normal tissue stroma, the collagen fibrils found in breast tissue are often thicker and align perpendicular to the tumor boundary, which is associated with malignant transformation and metastatic progression.(72,95) This non-random orientation o”
Illuminating the metastatic process (2007, neutral): “This field will also benefit from correlative live imaging, immunohistochemistry and electron microscopy analysi”
Extracellular matrix: a dynamic niche component during cancer progression (2012, neutral): “…different from that of the normal tissue stroma; rather than relaxed nonoriented fibrils, the collagen I in breast tumors is often highly linearized and either oriented ad jacent to the epithelium or projecting perpendicularly into the tissue (Provenzano et al., 2006; Levental et al., 2009).”