Targeting ECM Disrupts Cancer Progression

Abstract

Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

Keywords: collagen I; extracellular matrix; hyaluronan; metastasis; periostin; tenascin C.

Figure 1

The ECM drives the progression of cancer cells along the metastatic cascade. The metastatic cascade is composed of multiple complex processes, which are critically influenced by ECM components. First, ECM-regulated signaling pathways increase cancer cell motility and promote the egress from the primary tumor. In addition, the stability of the endothelial cell barrier is critically regulated by HA, thus influencing intra- and extravasation efficacy of cancer cells. The survival in the circulation system is also directly and indirectly modulated by ECM components as they function as physical shields as well as attractants for platelets. Through deposition and modification of ECM components at distant sites, the initial engraftment and final colonization of cancer are enhanced. Hereby, biochemical as well as biomechanical cues of the ECM promote metastatic outgrowth.

Figure 2

Escaping the primary tumor: ECM components induce cancer cell motility. In order to leave the primary tumor, cancer cells undergo epithelial-to-mesenchymal transition (EMT), which can be induced by ECM proteins and GAGs activating receptor-mediated signaling pathways. First, HA binding to CD44 on tumor cells induces EMT through the translocation of the receptor to the nucleus. CD44 is then able to induce a transcriptional upregulation of LOX. LOX promotes EMT by regulating the EMT transcription factor TWIST-1 through two mechanisms. First, LOX is able to activate the expression of TWIST-1. In addition, the activity of TWIST-1 is indirectly enhanced by LOX through association of cross-linked collagen I with integrin β1 and DDR2, which promotes the nuclear translocation of cytoplasmatic-bound TWIST-1. Besides, tenascin C also influences the transcriptional regulation of EMT indicated by the downregulation of E-cadherin and a simultaneous upregulation of vimentin as well as several MMPs. Periostin also enhances MMP expression, thus inducing EMT through binding to tumor cell α_vβ₅-integrin.

Figure 3

Survival in the blood: ECM components as physical shields and mediators of platelet recruitment. In order to survive the high shear forces and patrolling NK-cells in the blood circulation, tumor cells interact with platelets. This association is mainly initiated by fibrinogen. Fibrinogen binding to tumor-expressed α_vβ₃ and platelet-derived integrin α_IIbβ₃ induces the formation of cancer-cell–fibrinogen–platelet complexes. In addition, tenascin C association with integrin α₂β₁ or the glycoprotein Ib-IX complex enhances platelet adhesion and activation. An HA-rich pericellular matrix further shields the cancer cells from NK-cell attack.

Figure 4

A distant home: tumor cell extravasation and engraftment at secondary sites are enhanced by ECM secretion and remodeling. Extravasation requires cancer cell adhesion to the vessel wall and an invasion into the foreign tissue. HA mediates an initial adherence as both endothelial and cancer cells bind to the GAG through CD44. A subsequent secretion of hyaluronidase breaks down HMW-HA. The local increase of LMW-HA disrupts the endothelial cell barrier supporting transendothelial migration of the cancer cells. After arrival at a distant site, cancer cells are exposed to a foreign environment. To allow survival under these different conditions, cancer cells secrete ECM components and ECM-remodeling enzymes to favor the engraftment at the foreign site. An example is tumor-derived LOX altering collagen cross-linking at pre-metastatic sites. Tumor cell-secreted tenascin C also enhances the establishment of micrometastases. However, tumor cells also induce stromal cells to produce cancer-promoting ECM proteins, creating a more permissive environment. Here, stromal periostin improves cancer cells adhesion by binding to αvβ5-integrin. In addition, periostin supports the self-renewal and proliferation of CSCs through the activation of the WNT signaling pathway, which may enhance outgrowth of metastases.

Figure 5

Final colonization: ECM deposition and remodeling facilitate the outgrowth of metastases. The final outgrowth of macrometastases is influenced by the deposition, remodeling, and signaling of ECM components. An example is the extensive secretion and alignment of collagen I fibers promoting the final colonization of cancer cells at a distant site. In addition, tumor-secreted LOX cross-links collagen IV, thereby attracting BMDCs. These cells indirectly enhance CSC survival and renewal. BMDC-secreted versican associates with HA. The complex can bind CD44 of macrophages activating their production of PDGF-BB. PDGF-BB in turn mediates other stromal cell secretion of FGF, which finally stimulates the proliferation of CSCs. In addition, versican also induces angiogenesis. An increase in angiogenic activity is also mediated by periostin. Tumor-secreted periostin binds integrin α_vβ₃ of endothelial and tumor cells. This activates PKB/AKT signaling, promoting cell survival enhancing angiogenesis as well as tumor cell outgrowth. Another mechanism supporting tumor cell survival is the induction of stromal tenascin C secretion. Tenascin C can activate WNT and NOTCH signaling pathways ensuring tumor cell viability under unpermissive conditions.