Biophysical Properties of Extracellular Matrix: Linking Obesity and Cancer

Abstract

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 the increased risk and severity of several types of cancer, including pancreatic, liver, colon and breast cancers [1]. 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 [2], recent findings indicate that the extracellular matrix (ECM) found in obese tissues may be similarly important. Here, we highlight key biochemical and biophysical characteristics of obese vs. 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.

ECM Physicochemical Properties Regulate Cell Function in the Obese Mammary Gland

The ECM holds critical responsibilities in mediating the proper development and homeostasis of tissues, and can govern both normal and cancer cell function and fate [3]. For example, ECM isolated from virgin rat mammary glands has been shown to exert anti-tumorigenic effects on breast cancer cells, while ECM isolated from involuting rat mammary glands is pro-tumorigenic [4]. Interestingly, the pro-tumorigenic effects of the latter are mediated by a mechanism of inflammatory signaling that can be inhibited by nonsteroidal anti-inflammatory drugs. As 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 [5]. Obese ECM has been shown to display increased levels of pro-fibrotic components, including collagen I and VI, fibronectin and hyaluronic acid (HA) [5,6]. 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 consequential 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. Similar to tumor-associated ECM, obese ECM is stiffer than its lean counterpart and can promote the malignant potential of mammary epithelial cells due to changes in mechanosignaling [5] 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 therapy response [5,7]. 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 the stress relaxing properties of the ECM [8]. Intriguingly, increased HA content during fibrotic ECM remodeling can simultaneously elevate the osmotic pressure within interstitial tissue [9], 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 [10]. Collectively, these variations in ECM biophysical properties can significantly affect resident cell behavior by modulating mechanosignaling, altering cell metabolism [11], providing routes for migratory cell transit, and generally affecting growth factor and cytokine signaling by altering solute transport.

Molecular Mechanisms Linking the Obese ECM to Cellular Responses

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 bi-directional interaction between cells and the ECM which potentiates the formation and maturation of focal adhesions [12]. 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/tafazzin (YAP/TAZ) [5]. Additionally, breast cancer cells interacting with stiff matrix translocate the transcription factor TWIST1 to their nucleus, which is canonically associated with the epithelial to mesenchymal transition (EMT), a phenotypic change involved in tumor invasion and metastasis [13]. 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 of the ECM between patient obesity and cancer severity. Along with this, epidemiological data has demonstrated that circulating tumor cells in breast cancer patients commonly display mesenchymal cell characteristics [14]. 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 [15]. Also, 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.

Figure 1. Obese Tissue Extracellular Matrix (ECM) Induces Invasive Traits in Breast Cancer Cells.

Obese tissue ECM is comprised of stiffened, aligned fibers and high interstitial pressure, as compared to lean tissue ECM. These changes can lead to hypoxic conditions in obese tissues, along with increased myofibroblast and macrophage content which further contribute toward the inflamed, fibrotic ECM phenotype. Breast cancer cell responses to obese ECM include the upregulation of invasive characteristics that may result in higher rates of metastases, thus providing intriguing therapeutic intervention points.

Future perspectives

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 for 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.