Biophysical Properties of Extracellular Matrix: Linking Obesity and Cancer
Authors: Joseph E. Druso, Claudia Fischbach
Journal: Trends in cancer (2018)

Obesity has been associated with increased severity of diagnoses for several types of cancer, and recent evidence suggests that the mechanism by which obese tissues contribute to cancer progression involves the extracellular matrix (ECM). Understanding the physicochemical differences between lean and obese ECM, and how cancer cells respond to these differences, promises therapeutic insight. Obesity has been associated with increased severity of diagnoses for several types of cancer, and recent evidence suggests that the mechanism by which obese tissues contribute to cancer progression involves the extracellular matrix (ECM). Understanding the physicochemical differences between lean and obese ECM, and how cancer cells respond to these differences, promises therapeutic insight. Worldwide obesity rates have nearly doubled in the past three decades and, along with elevating the risk for cardiovascular and diabetic diseases, obesity has also been linked with increased risk and severity of several types of cancer, including pancreatic, liver, colon, and breast cancers [1Steele C.B. et al.Vital signs: trends in incidence of cancers associated with overweight and obesity – United States, 2005–2014.Morb. Mortal. Wkly. Rep. 2017; 66: 1052-1058Crossref PubMed Scopus (212) Google Scholar]. While much current work focuses on elucidating how obesity-mediated alterations of adipose endocrine functions promote tumorigenesis by altering local and systemic levels of adipokines, hormones, and cytokines [2Hopkins B.D. et al.Obesity and cancer mechanisms: cancer metabolism.J. Clin. Oncol. 2016; 34: 4277-4283Crossref PubMed Scopus (163) Google Scholar], recent findings indicate that the ECM found in obese tissues may be similarly important. Here, we highlight key biochemical and biophysical characteristics of obese versus lean ECM and the molecular mechanisms that cells explore to translate these differences into altered cellular behavior, suggesting distinct roles for obese ECM during tumorigenesis and providing new therapeutic considerations. The ECM holds crucial responsibilities in mediating the proper development and homeostasis of tissues, and can govern both normal and cancer cell function and fate [3Frantz C. et al.The extracellular matrix at a glance.J. Cell Sci. 2010; 123: 4195-4200Crossref PubMed Scopus (2383) Google Scholar]. For example, ECM isolated from virgin rat mammary glands has been shown to exert antitumorigenic effects on breast cancer cells, while ECM isolated from involuting rat mammary glands is protumorigenic [4O'Brien J. et al.Non-steroidal anti-inflammatory drugs target the pro-tumorigenic extracellular matrix of the postpartum mammary gland.Int. J. Dev. Biol. 2011; 55: 745-755Crossref PubMed Scopus (43) Google Scholar]. Interestingly, the protumorigenic effects of the latter are mediated by a mechanism of inflammatory signaling that can be inhibited by nonsteroidal anti-inflammatory drugs. Because obese breast tissue is considered to be chronically inflamed, it is perhaps not surprising that obesity-associated ECM remodeling can also directly contribute to tumor progression [5Seo B.R. et al.Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.Sci. Transl. Med. 2015; 7301ra130Crossref PubMed Scopus (190) Google Scholar]. Obese ECM has been shown to display increased levels of profibrotic components, including collagen I and VI, fibronectin, and hyaluronic acid (HA) [5Seo B.R. et al.Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.Sci. Transl. Med. 2015; 7301ra130Crossref PubMed Scopus (190) Google Scholar, 6Sun K. et al.Fibrosis and adipose tissue dysfunction.Cell Metab. 2013; 18: 470-477Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar]. While the biochemical effects of obesity-mediated alterations in ECM composition have become a focus of research, the resulting biophysical changes in the ECM and consequent effects on tumor progression may be similarly important. In particular, altered ECM mechanical properties caused by fibrotic remodeling are widely investigated as a direct mechanism for increased tumor development and progression. Similarly to tumor-associated ECM, obese ECM is stiffer than its lean counterpart and can promote the malignant potential of mammary epithelial cells via changes in mechanosignaling [5Seo B.R. et al.Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.Sci. Transl. Med. 2015; 7301ra130Crossref PubMed Scopus (190) Google Scholar]. Increased stiffness of obese ECM is due in part to the presence of thicker and more aligned collagen fibers that influence tumor growth, invasion, and response to therapy [5Seo B.R. et al.Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.Sci. Transl. Med. 2015; 7301ra130Crossref PubMed Scopus (190) Google Scholar, 7Provenzano P.P. et al.Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization.Biophys. J. 2008; 95: 5374-5384Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar]. Importantly, tumoral and stromal cells can respond to these microstructural differences of the matrix network with strain-induced fiber alignment, which further stiffens the ECM and thus promotes malignant behavior. On the other hand, obesity-mediated variations in ECM composition such as increased HA content can stimulate tumor cell aggression by impacting on the stress-relaxing properties of the ECM [8Lou J. et al.Stress relaxing hyaluronic acid–collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture.Biomaterials. 2018; 154: 213-222Crossref PubMed Scopus (268) Google Scholar]. Intriguingly, increased HA content during fibrotic ECM remodeling can simultaneously elevate the osmotic pressure within interstitial tissue [9Provenzano P.P. Hingorani S.R. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer.Br. J. Cancer. 2013; 108: 1-8Crossref PubMed Scopus (218) Google Scholar], potentially leading to blood vessel collapse. Impaired blood supply, in turn, further aggravates obesity-induced hypoxia, which may additionally stiffen the ECM by hypoxia-inducible factor 1α (HIF 1α)-stimulated lysyl oxidase (LOX) activity [10Erler J.T. et al.Lysyl oxidase is essential for hypoxia-induced metastasis.Nature. 2006; 440: 1222-1226Crossref PubMed Scopus (1148) Google Scholar]. Collectively, these variations in ECM biophysical properties can significantly affect resident cell behavior by modulating mechanosignaling, altering cell metabolism [11Morris B.A. et al.Collagen matrix density drives the metabolic shift in breast cancer cells.EBioMedicine. 2016; 13: 146-156Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar], providing routes for migratory cell transit, and generally affecting growth factor and cytokine signaling by altering solute transport. In response to increased substrate stiffness, cells can adjust their contractile forces and exert further strain on their attachments to the ECM, resulting in a bidirectional interaction between cells and the ECM which potentiates the formation and maturation of focal adhesions [12Yim E.K. Sheetz M.P. Force-dependent cell signaling in stem cell differentiation.Stem Cell Res. Ther. 2012; 3: 41Crossref PubMed Scopus (109) Google Scholar]. Indeed, resident cells within our tissues explore sophisticated cell-signaling cascades to interpret ECM physicochemical properties through mechanotransduction. One key example is through integrins within the plasma membrane of cells that can bind to the ECM, leading to integrin clustering and the initiation of intracellular signals that act as an 'outside-in' form of cell signaling. These signals include focal adhesion kinase (FAK), Src, Rho kinase (ROCK), and myosin light chain kinase (MLCK) activation, which can ultimately affect cell behavior and identity, such as through increasing mitogen-activated protein kinase (MAPK) activity and the nuclear accumulation of oncogenic transcription factors Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) [5Seo B.R. et al.Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis.Sci. Transl. Med. 2015; 7301ra130Crossref PubMed Scopus (190) Google Scholar]. In addition, breast cancer cells interacting with stiff matrix translocate the transcription factor TWIST1 to their nuclei, which is canonically associated with the epithelial to mesenchymal transition (EMT), a phenotypic change involved in tumor invasion and metastasis [13Wei S.C. et al.Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway.Nat. Cell Biol. 2015; 17: 678-688Crossref PubMed Scopus (544) Google Scholar]. It is compelling to consider that the complex signals provided by the ECM are capable of inducing mesenchymal cell traits within tumor cells, suggesting a mechanistic link among the ECM, patient obesity, and cancer severity. Furthermore, epidemiological data have demonstrated that circulating tumor cells in breast cancer patients commonly display mesenchymal cell characteristics [14Yu M. et al.Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition.Science. 2013; 339: 580-584Crossref PubMed Scopus (1815) Google Scholar]. Taken together, a broader view of how obesity affects breast cancer metastasis emerges in which obese mammary ECM may provide permissive conditions for invasive traits to arise in tumor cells as well as accessible routes of transit away from the primary tumor. Furthermore, while obese ECM can have direct effects on tumor cells, fibroblasts have also been shown to transition toward a myofibroblast phenotype in obese mouse tissues, which is then capable of further potentiating inflammatory conditions and aberrant ECM deposition [15Incio J. et al.Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy.Cancer Discov. 2016; 6: 852-869Crossref PubMed Scopus (229) Google Scholar]. In addition, as obese mammary gland adipocytes proliferate and enlarge, their physical expansion limits blood supply and can ultimately result in adipocyte death and macrophage recruitment in crown-like structures. Collectively, the changes in myofibroblast, adipocyte, and macrophage content within obese mammary glands further promote inflammatory signaling and altered ECM deposition within the tissue, which may create an advantageous niche for tumor cell growth and migration (Figure 1). Cancer metastases are a primary cause of patient mortality due to the aggressiveness and chemotherapy-resistance of the recurring tumors, stressing the importance of understanding these intriguing effects of obese ECM on tumor and microenvironment cell behavior. The relationship between obesity and breast cancer is complex, and demands further understanding of the mechanisms by which one genome is used to produce these varied types of interacting cells. Research on the relationship between obesity and breast cancer has begun to highlight the ECM as a dynamic and powerful orchestrator of gene expression, tissue homeostasis, and therefore disease progression. Given the rising evidence of the influential role played by the ECM in tissue homeostasis, the exact composition and relative protein abundance of this biological matrix, as well as the resulting consequences on ECM biophysical properties (referred to as the 'matrisome'), have become central to understanding cancer development and progression, and present compelling new ideas for therapeutic targets. Could the reprogramming of resident stromal cells within obese tissue, or even targeted therapeutics, allow ECM remodeling that results in fewer metastases and more favorable patient prognoses? New technologies that allow researchers to isolate native ECM from lean and obese patients for characterization and functional analyses, mimic these properties with artificial ECMs of defined stiffness and microstructure, and analyze cell signaling responses to these substrates are collectively blazing new trails of research that enable novel discoveries with the ultimate goal of improving the diagnosis and treatment of obesity-associated cancer. This work was supported by the Center on the Physics of Cancer Metabolism through Award Number 1U54CA210184 from the National Cancer Institute and 1 R01 CA185293.