The two faces of enhanced stroma: Stroma acts as a tumor promoter and a steric obstacle

Abstract

In addition to genetic, morphological and biochemical alterations in cells, a key feature of the malignant progression of cancer is the stroma, including cancer cell motility as well as the emergence of metastases. Our current knowledge with regard to the biophysically driven experimental approaches of cancer progression indicates that mechanical aberrations are major contributors to the malignant progression of cancer. In particular, the mechanical probing of the stroma is of great interest. However, the impact of the tumor stroma on cellular motility, and hence the metastatic cascade leading to the malignant progression of cancer, is controversial as there are two different and opposing effects within the stroma. On the one hand, the stroma can promote and enhance the proliferation, survival and migration of cancer cells through mechanotransduction processes evoked by fiber alignment as a result of increased stroma rigidity. This enables all types of cancer to overcome restrictive biological capabilities. On the other hand, as a result of its structural constraints, the stroma acts as a steric obstacle for cancer cell motility in dense three-dimensional extracellular matrices, when the pore size is smaller than the cell's nucleus. The mechanical properties of the stroma, such as the tissue matrix stiffness and the entire architectural network of the stroma, are the major players in providing the optimal environment for cancer cell migration. Thus, biophysical methods determining the mechanical properties of the stroma, such as magnetic resonance elastography, are critical for the diagnosis and prediction of early cancer stages. Fibrogenesis and cancer are tightly connected, as there is an elevated risk of cancer on cystic fibrosis or, subsequently, cirrhosis. This also applies to the subsequent metastatic process.

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

“…For instance, collagen matrices can restrict tumour cell proliferation [129][130][131][132][133][134][135][136] . Consistent with this view 128 , we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma 48 , breast cancer 76,78 , and lung cancer cells 74,75 . The mechanisms for the anti-proliferative effects of DDRs and COL1 in vitro are still poorly understood, however previous studies have shown that this process may include induction of cell cycle arrest 48,75 or apoptosis 77,78 .…”

“…Also, a number of studies utilized collagen I gels to inoculate tumour cells in vivo [81][82][83][84] , demonstrating a tumour-promoting effect of collagen. Yet, evidence indicate that collagen matrices can elicit divergent effects on tumour cells by either promoting or suppressing malignant activity 128 . For instance, collagen matrices can restrict tumour cell proliferation [129][130][131][132][133][134][135][136] .…”

An Organotypic Mammary Duct Model Capturing Distinct Events of DCIS Progression

“…We also found that varying collagen concentration-our preliminary model of desmoplasia-alters invasive and clustering behaviors. Our findings confirm the dual roles of an activated extracellular matrix as a steric obstacle and a promoter 56 .…”

“…Higher collagen concentration is typically associated with denser matrices with smaller pore sizes 56,57 . The nature of such a matrix to act as an obstacle has been observed in the decreased the number of MDA-MB-231 cells invading into collagen matrices 39 , which we also observed ( Figure 2B).…”

“…Several factors have been proposed to contribute to promoting cell invasiveness in higher collagen concentrations. These include increased rigidity of the matrix, allowing cells to generate the forces necessary for spreading and migration 56 or increase their MMP activity 59 , and increased collagen fiber alignment that could direct cancer cell protrusion rate, and thereby motility 57 .…”