Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

Grossman, Moran; Ben-Chetrit, Nir; Zhuravlev, Alina; Afik, Ran; Bassat, Elad; Solomonov, Inna; Yarden, Yosef; Sagi, Irit

doi:10.1158/0008-5472.can-15-2813

Cited by 113 publications

(97 citation statements)

References 46 publications

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“…The artificial vessel ring collagen was detected using second harmonic generation (SHG) microscopy, and VSMCs were stained for α SMA (A2547 Sigma‐Aldrich, St. Louis, MO, USA) and then imaged (Jena Germany) as described (Grossman et al., 2016). Volocity image analysis software (Perkin Elmer, Waltham, MA, USA) was then used to segment the VSMCs in 3D based upon a‐SMA staining and calculate the respective parameters of VSMCs automatically with the captured 3D cell images (Porter, Holt, Soong, Shanahan & Warren, 2016).…”

Section: Methodsmentioning

confidence: 99%

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Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Hays

Zhou

et al. 2018

Aging Cell

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SummaryAortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffening through their extracellular effects. Aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) vs. Wistar‐Kyoto (WKY) rats in vivo by echocardiography and ex vivo by isometric force measurements in isolated de‐endothelized aortic vessel segments. Vascular smooth muscle cells were isolated from thoracic aorta and embedded in a collagen I matrix in an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. SHR VSMCs increased the synthesis of collagen and induced collagen fibril disorganization in reconstituted vessels. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin β1‐ and bone morphogenetic protein 1 (BMP1)‐mediated proteolytic cleavage of lysyl oxidase (LOX). These VSMC‐induced alterations in the SHR were attenuated by an inhibitor of serum response factor (SRF)/myocardin. Therefore, SHR VSMCs exhibit extracellular dysregulation through modulating integrin β1 and BMP1/LOX via SRF/myocardin signaling in aortic stiffening.

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Section: Methodsmentioning

confidence: 99%

“…Imaging analysis for collagen directionality was done by Fiji package (Schindelin et al., 2012). Fourier component analysis for directionality was performed on data using the Fiji plug‐in “Directionality” and following manufacturer's instructions (Grossman et al., 2016). …”

Section: Methodsmentioning

confidence: 99%

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Hays

Zhou

et al. 2018

Aging Cell

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“…Additional studies revealed that collagen fiber alignment can predict cell motility, relative to the pore size and density (Fraley et al 2015), and that an increase in protrusion frequency, persistence, and lengthening along the direction of the fibers depends on FAK and Rac1 signaling (Carey et al 2016). Indeed, preventing collagen alignment by inhibiting the activity of the collagen cross-linker LOXL2 (Grossman et al 2016), or through knockdown of the proteoglycan syndecan1 (Yang et al 2011), but not by inhibiting protease activity (matrix metalloproteinases [MMPs] and serine and cysteine proteases), reduced the directional migration of tumor cells in vitro and in vivo (Wyckoff et al 2006;Levental et al 2009;Rubashkin et al 2014). Thus compelling in vitro and in vivo data attest to the importance of alignotaxis as a regulator of the local invasion of tumor cells.…”

Section: Alignotaxismentioning

confidence: 99%

“…For instance, inhibition of LOX through pharmacological inhibition or injection with lysyl oxidase (LOX)-neutralizing antibodies reduced tumor metastasis from solid tumors (Levental et al 2009;Cox et al 2013;Pickup et al 2013). Similarly, studies using function-blocking antibodies to inhibit lysyl oxidase-like 2 (LOXL2) reduced collagen alignment and decreased tumor burden in a breast tumor xenograft (Grossman et al 2016); these antibodies have been associated with invasiveness and poor outcome in breast cancer (Ahn et al 2013). Higher LOXL2 levels are also associated with tumor invasion and poor outcome in pancreatic cancer patients and showed some efficacy in mouse models of PDAC (Park et al 2016).…”

Section: Disrupting the Gradientmentioning

confidence: 99%

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Oudin

Weaver

2016

Cold Spring Harb Symp Quant Biol

158

121

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Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients. These gradients form through dynamic interactions between the tumor cells and the resident fibroblasts, adipocytes, nerves, endothelial cells, infiltrating immune cells, and mesenchymal stem cells. Malignant progression results from the integrated response of the tumor to these extrinsic physical and chemical cues. Here, we first describe how these physical and chemical gradients develop, and we discuss their role in tumor progression. We then review assays to study these gradients. We conclude with a discussion of clinical strategies used to detect and inhibit these gradients in tumors and of new intervention opportunities. Clarifying the role of these gradients in tumor evolution offers a unique approach to target metastasis.Tumors are highly heterogeneous and this feature compromises treatment efficacy and promotes tumor cell dissemination and metastasis to reduce patient survival. Tumor heterogeneity is driven in part by genetic alterations induced through genomic instability and maintained by the evolutionary selection of these genetically modified cells (Alizadeh et al. 2015). Epigenetic, transcriptional, and posttranslational modifications also contribute significantly to tumor cell diversity. Furthermore, cancer develops within a complex tissue microenvironment that itself fosters tumor heterogeneity through clonal selection as well as via epigenetic reprogramming and modifications of the tumor phenotype. The tumor microenvironment is composed of cellular constituents that include cells of the vasculature, infiltrating immune cells, and resident fibroblasts, adipocytes and nerves, and a noncellular component composed of diverse soluble factors and a highly variable and evolving insoluble extracellular matrix (ECM) (Joyce and Pollard 2009). The composition and organization of the tumor microenvironment vary significantly within and across tumors.One key feature of the noncellular microenvironment is the existence of local chemical and physical gradients that exert profound effects on the tumor phenotype, including its predilection to disseminate. In this regard, metastasis is facilitated by efficient local tumor cell invasion that is fostered by ECM and chemokine/cytokine/growth factor gradients which cooperate to promote the directional migration of the t...

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“…This limitation is problematic because fibers may play important roles in directing cell behavior; for example, fibrillar alignment of collagen in breast tumors has been shown to correlate with a worse patient prognosis [31, 32]. The influence of fibrillar structure on cellular outcomes was also highlighted by recent work which described a significant decrease in mouse xenograft tumor growth upon attenuation of fiber formation and crosslinking by inhibition of LOXL2 [33]. Here, we report a novel method for fabricating an interpenetrating network (IPN) hydrogel of gelMA and collagen I which allows for a wide variation of shear modulus while retaining the fibrillar structure of collagen.…”

Section: Introductionmentioning

confidence: 99%

Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen

et al. 2017

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The extracellular microenvironment provides critical cues that guide tissue development, homeostasis, and pathology. Deciphering the individual roles of these cues in tissue function necessitates the development of physically tunable culture platforms, but current approaches to create such materials have produced scaffolds that either exhibit a limited mechanical range or are unable to recapitulate the fibrous nature of in vivo tissues. Here we report a novel interpenetrating network (IPN) of gelatin-methacrylate (gelMA) and collagen I that enables independent tuning of fiber density and scaffold stiffness across a physiologically-relevant range of shear moduli (2–12 kPa), while maintaining constant extracellular matrix content. This biomaterial system was applied to examine how changes in the physical microenvironment affect cell types associated with the tumor microenvironment. By increasing fiber density while maintaining constant stiffness, we found that MDA-MB-231 breast tumor cells required the presence of fibers to invade the surrounding matrix, while endothelial cells (ECs) did not. Meanwhile, increasing IPN stiffness independently of fiber content yielded decreased invasion and sprouting for both MDA-MB-231 cells and ECs. These results highlight the importance of decoupling features of the microenvironment to uncover their individual effects on cell behavior, in addition to demonstrating that individual cell types within a tissue may be differentially affected by the same changes in physical features. The mechanical range and fibrous nature of this tunable biomaterial platform enable mimicry of a wide variety of tissues, and may yield more precise identification of targets which may be exploited to develop interventions to control tissue function.

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Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

Cited by 113 publications

References 46 publications

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis

Decoupling the effects of stiffness and fiber density on cellular behaviors via an interpenetrating network of gelatin-methacrylate and collagen

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