Decorin as a multivalent therapeutic agent against cancer☆
Graphical abstract
Introduction
Fundamental for all facets of multicellular life and evolutionarily conserved, the extracellular matrix (ECM) is a diverse network of instructional cues linking the local tissue microenvironment with the juxtaposed tumor cells [1], [2], [3]. Emerging as a critical entity in chemotherapeutics, tumorigenic progression, and predicting clinical outcome [4], [5], [6], the ECM is a nexus of signal integration for a plethora of cell-derived factors while synchronously regulating cellular behaviors [7]. This symbiotic relationship facilitates bidirectional parsing of intrinsic biological information into functionally relevant processes responsible for orchestrating tumorigenesis and angiogenesis [8], [9], [10].
The small leucine-rich proteoglycans (SLRPs) are an emerging subset of matrix-derived, soluble regulators that are inextricably woven into the fabric of the ECM. They reflect the multifactorial propensity of the matrix, and subsume crucial roles over a spectrum of homeostatic and pathological conditions [11]. This 18-member strong gene family is proving critical for restraining the development, progression, and dissemination of various solid tumors [12], [13], [14]. Decorin, the archetypical SLRP, harbors a single, covalently attached N-terminal glycosaminoglycan (GAG) chain consisting of either dermatan or chondroitin sulfate, twelve leucine-rich tandem repeats (LRR), and a class-specific C-terminal Ear domain [15]. Although the crystal structure of decorin has been solved as a head-to-tail dimer [16], it is likely that soluble decorin is active as a monomer in solution [17], [18].
Decorin was originally discovered as an avid collagen-binding protein necessary for appropriate fibrillogenesis [19], [20], [21], [22], thereby originating the eponym of decorin [15]. Akin with a role in orchestrating and ensuring proper collagen fibril network assembly, decorin regulates tissue integrity by modulating key biomechanical parameters of tendons and skin [23], [24], [25], [26]. However, seminal work heralded a major paradigm shift in understanding the function of SLRPs by demonstrating that soluble decorin is a high-affinity, antagonistic ligand for several key receptor tyrosine kinases resulting in protracted oncostasis and angiostasis [27]. As a further mechanism for the oncosuppressive propensities of decorin, numerous growth factors—e.g. TGF-β [28], [29] and CCN2/CTGF [30], to name a few—and matrix constituents are sequestered [31] and manifest as an indirect attenuation of downstream signaling apparati. More recently, decorin has emerged as a soluble pro-autophagic cue by initiating endothelial cell autophagy and evoking tumor cell mitophagy as the mechanistic basis for the documented oncostatic effects [32]. Cumulatively, decorin is a soluble tumor repressor and anti-angiogenic factor and has rightfully earned the designation of “a guardian from the matrix” [31].
Beyond the emerging literature regarding the role of decorin within the tumor stroma, decorin is genuinely a multifaceted signaling effector and exemplifies the growing role of SLRPs in organismal homeostasis and pathology. Germane examples include immunomodulation [33], [34], cutaneous wound healing [35], proper keratinocyte function [36], diabetic nephropathies [37], fetal membrane homeostasis [38], obesity and type II diabetes [39], allergen-induced asthma [40], allergic inflammation [41], delayed hypersensitivity reactions [42], hepatic fibrosis [43], myogenesis and muscular dystrophy [44], [45], post-myocardial infarction remodeling [46], and mediating proper vertebrate convergent extension [47]. Moreover, decorin has been identified as a potential biomarker for ischemic stroke [48], renal and pulmonary diseases [49], [50], [51], and for maintaining hematopoietic stem cell niches [52].
In this review, we will critically evaluate decorin as a tumoricidal agent by examining the classical mechanisms of decorin-mediated oncogenic suppression and the newly discovered signaling pathways that are exploited for autophagic induction. The biofunctionality of decorin and associated mechanisms discussed herein represent novel targets for future therapeutic intervention, as derived from this versatile proteoglycan, that will satisfy a growing and unmet medical need.
An important construct for understanding the anti-tumorigenic effects of decorin concerns the localization and corresponding expression patterns of this prototypical SLRP within the various tumorigenic compartments [53].
Despite a large literature describing decorin as an oncosuppressive proteoglycan [12], [13], [31], [54], there are still several incongruences that need to be addressed. In particular, the absence of decorin in the breast tumor stroma has been established as an important clinical prognosticator of invasive and metastatic breast cancer [10], [55], [56], [57] as well as in soft tumors [58]. A similar reduction of decorin expression is seen in the microenvironments of low- and high-grade urothelial carcinoma [59] as well as in the plasma of multiple myeloma and MGUS patients [60], cases of esophageal squamous cell carcinoma [61], and instances of colon cancer [53]. An in silico–based query utilizing immunohistochemical arrays spanning a variety of tissues has detected a marked reduction of decorin expression in the stroma of many solid malignancies, including breast [62]. Other studies seemingly report the opposite results inasmuch as certain tumor types, including colon and breast carcinomas [54], have elevated amounts of stromally deposited decorin. Functionally, the increased caches of decorin within these tumors may still negatively regulate growth by physically constraining the tumor (e.g. desmoplastic-type reactions) as well as acting in a paracrine manner to downregulate the adjacent RTKs present on the tumor cell surface. As it pertains to the tumor proper, several studies have clearly demonstrated a complete loss of decorin expression in several tumor types, such as urothelial, prostate, myeloma, and hepatic carcinoma [63], [64], [65], [66], [67], [68]. Utilizing an unbiased deep RNA sequencing method of hepatocellular carcinomas, several prominent matrix constituents were decreased, including decorin [69]. Moreover, poorly differentiated sarcomas completely lack decorin in contrast to hemangiomas which have considerable expression of decorin [66]. Therefore, the malignancy of a tumor may be linked to endogenous decorin expression.
As mentioned in Section 1.1.1, decorin is found to be profusely expressed within the stroma of colon cancer. This was the very first indication of a possible connection between decorin and an oncogenic setting [70], [71], [72]. Like p53, decorin was initially perceived as an oncogene. Since this discovery, strong genetic evidence has emerged confirming the oncostatic role of decorin following the unconditional ablation of decorin from the M. musculus genome [73]. Mice lacking the Dcn gene and given a Western diet (e.g. high fat) develop intestinal tumors [74]. Mechanistically, loss of decorin disrupts appropriate intestinal cell maturation, leading to aberrant turnover (decreased differentiation and increased proliferation consistent with suppressed p21 and p27 with elevated β-catenin) of the intestinal epithelium [74]. Moreover, the inhibition of colon carcinoma by decorin involves modulating E-cadherin levels in vitro and in vivo [75]. Moreover, when both p53 and Dcn genes are concurrently ablated, there is a genetic cooperation demonstrated by the rapid onset of aggressive T-cell lymphomas and premature death of the double mutant mice [76]. These studies indicate that genetic loss of decorin is permissive for tumorigenic initiation.
Several studies have been completed wherein decorin is potently anti-metastatic for breast carcinomas [56], [57], [77] while compromising otherwise rampant tumor angiogenesis [78], [79]. In a murine model of osteosarcoma, decorin prevents lung metastases [80] and inhibits B16V melanoma cell migration [81]. Of clinical and therapeutic importance, re-introduction of decorin via adenoviral delivery, de novo ectopic expression, or systemic administration counteracts the tumorigenicity in several animal models of cancer that recapitulate solid neoplastic growth [82], [83], [84], [85], [86], [87], [88]. Notably, preclinical studies using infrared-labeled decorin have shown that it preferentially targets the tumor xenografts with prolonged retention of the active agent [89]. Recently, adenoviral-mediated decorin expression has been shown to decrease the growth of bone metastases caused by intracardiac injections of prostate [90] and breast [91] carcinomas. Taken together, the aforementioned genetic and preclinical studies establish and authenticate decorin as a viable tumor repressor for combating several types of cancer.
Section snippets
Decorin structure: high-affinity interactions with several receptors
Harboring the largest known gene family of proteoglycans, decorin and related classes of SLRPs share a common core architecture [92]. They are ubiquitously expressed in all major organs during development [93], and are present within all matrix assemblies. The various members have been organized into five distinct classes based on the criteria of evolutionarily conserved structural homology (including organization at the genomic and protein levels) as well as by shared functional properties [15]
Suppression of growth and tumor angiogenesis via EGFR and Met
Innate and distinct biological information pertinent for abrogating tumorigenic growth and suppressing tumor angiogenesis is stored within the solenoid structure of decorin [31]. This information is interpreted and transduced via engagements to a specific subset of RTKs (Fig. 2) that are amplified and enriched within the tumor parenchyma [10], [12]. In the context of Met and EGFR, monomeric decorin [17] binds a narrow region that partially overlaps with that of the agonist binding cleft [111].
Decorin ameliorates tumorigenesis by evoking stromal autophagy and tumor mitophagy
A major breakthrough in deciphering the in vivo bioactivity of decorin came from a preclinical screen that sought novel decorin-regulated genes [88]. With this goal, triple-negative breast carcinoma orthotopic xenografts were established and treated systemically with decorin, for downstream utilization on a high-resolution transcriptomic platform [88]. Unlike traditional microarrays, this chip was designed for the simultaneous analysis and detection of species-specific genes modulated within
Gene and protein therapy in various preclinical tumor studies
Delivery of decorin via adenovirus (Ad) vectors, together with the systemic administration of decorin proteoglycan or protein core, has been tested in a variety of preclinical studies. In Table 1, we summarize past and current studies utilizing these two approaches focused exclusively on cancer treatment and delivery. Although the therapeutic efficacy varies among these studies, it is clear that decorin has a deleterious effect on growth, apoptosis, metabolism, and angiogenesis.
This concept was
Conclusions
The extracellular matrix is rapidly emerging as a crucial component for better understanding fundamental cellular processes and behaviors as well as providing novel therapeutic targets for combating complex pathological conditions [6] after these pathways have gone awry. Our pursuit of comprehending the varied intricacies and subtleties of reciprocal cell:matrix signaling for homeostatic and tumorigenic processes has been facilitated by an exhaustive proteomics approach, organized into an
Acknowledgements
The original research was supported in part by National Institutes of Health Grants RO1 CA39481, RO1 CA47282 and RO1 CA164462 (R.V.I.), and by grants from the German Research Council SFB 815, project A5, SFB 1039, project B2, and Excellence Cluster ECCPS (L.S.).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Extracellular Matrix (ECM) and ECM-like materials: Therapeutic Tools and Targets in Cancer Treatment”.