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Obesity-Associated Extracellular Matrix Remodeling: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Junyan Li.

Accumulated evidence has demonstrated that adipocytes can transform or de-differentiate into myofibroblast/fibroblast-like cells, which play vital roles in obesity-related extracellular matrix (ECM) remodeling and cancer progression. Adipose tissue, an energy storage and endocrine organ, is emerging as an essential player for ECM remodeling. Fibrosis is one of the hallmarks of obese adipose tissue, featuring excessive ECM deposition and enhanced collagen alignment. A variety of ECM components and ECM-related enzymes are produced by adipocytes and myofibroblasts in obese adipose tissue.

  • ECM remodeling
  • fibrosis
  • adipocyte plasticity
  • obesity

1. Introduction

Obesity is epidemiologically linked to the development of 13 different types of cancer, including breast cancer, gastric cancer, pancreas cancer, and melanomas [1]. It is estimated that obesity is associated with 20% of cancer-related deaths [2]. Obesity-dependent cancer development and progression involve inflammation, adipokines, microbiota, hyperinsulinemia, and IGF-1 signaling, which has been extensively summarized and reviewed [3,4,5][3][4][5]. In thiRes review, weearchers focused on recent progress in the function and regulation of obesity-associated extracellular matrix (ECM) remodeling and adipocyte plasticity during cancer progression.
The development of obesity requires continuous and adequate energy availability. Adipose tissue, as an energy storage and endocrine organ, is emerging as an essential player for systemic metabolic homeostasis. A key factor in the development from lean to obese is the dynamic response of adipose tissue to excessive nutrients. The direct and indirect interaction between adipose tissue and tumors is crucial for obesity-associated cancer development and progression [6]. It is well-established that adipose tissue is an active endocrine organ; adipokines and chemokines secreted by adipocytes serve as endocrine and paracrine cues to induce cancer progression. Adipose tissue also enhances free fatty acid uptake in cancer cells, facilitates the immune escape, and contributes to the fibrosis process in the tumor microenvironment [7,8][7][8].
Obese adipose tissue features an excessive deposition of the ECM components caused by an imbalanced synthesis of the fibrous components (such as collagen I, III, and VI) and matrix metalloproteinases (MMPs) [7]. Adipocytes, myofibroblasts, and fibroblasts are the major cellular components in the adipose tissue responsible for ECM production. Excessive collagen deposition and enhanced collagen alignment in adipose tissue have been observed in various models of obesity [9,10,11,12,13][9][10][11][12][13]. The connection between the fibrotic pathology and obesity-related metabolic disorders has been established [14,15][14][15]. Tissue fibrosis is a trigger for solid tumor development and progression [16]. Tumor migration/invasion and poor patient survival are related to tissue fibrosis and interstitial stiffness [17]. Recent studies have demonstrated that obesity-associated ECM deposition and alignment promote cancer development and progression [14,15][14][15].
Adipocyte differentiation was considered to be a terminal differentiation. However, recent studies have shown that adipocytes maintain plasticity and can de-differentiate into pre-adipocytes or fibroblast-like cells [10,18,19,20][10][18][19][20]. Adipocyte-derived fibroblasts were first reported upon the co-culture of 3T3-F442A adipocytes with breast cancer cells in vitro [21]. The adipocytes acquired a fibroblast-like morphology featuring an enhanced secretion of fibronectin and collagen I as well as an increased expression of the fibroblast-like biomarker FSP1 after co-culturing [21,22][21][22]. Data from lineage-tracing mouse models and a single-cell analysis showed that the de-differentiation of adipocytes occurs during mammary gland development, wound healing, and cancer development [13,21,23,24,25,26][13][21][23][24][25][26]. Notably, adipocytes adopted a fibroblast-like phenotype in obese mice with an enhanced expression of ECM-associated genes and ECM remodeling enzymes [10], suggesting that adipocyte plasticity is involved in obesity-associated fibrosis in adipose tissue.
The ECM is a major component in the tumor microenvironment that controls cancer development and progression [27,28,29][27][28][29]. Obesity-associated tumor development is partially driven by ECM remodeling in adipose tissue, which involves an increased deposition of the ECM and the enhanced crosslinking of collagen fibers [14,15][14][15]. Collagen VI has been identified from obese mammary fat tissue as the driver of cancer cell migration and invasion [14]. Evidence from tissue culture experiments suggests that an obese-associated mechanic alteration of the ECM in adipose tissue increased the malignant potential of mammary epithelial cells [15]. These studies demonstrate that the biochemical and biophysical cues from an altered ECM in adipose tissue promote tumorigenesis and enhance cancer cell invasion and migration [15].

2. Obesity-Associated Fibrosis and ECM Remodeling

Many ECM molecules and ECM-related enzymes have been identified in adipose tissue, including collagen [11[11][30][31][32],30,31,32], MMPs [33], and fibronectin [34,35][34][35]. Given the important function of the ECM in regulating cellular functions and differentiation, it is important to identify the components that are involved in obesity-associated ECM reorganization [7]. Among those ECM components, collagen and fibronectin are the most abundant ECM proteins in adipose tissue [36]. MMPs cleave collagenous proteins to enable an ECM turnover; MMP expression is also dysregulated in adipose tissue during obesity development [7] (Table 1). The deregulation of these three components disrupts ECM hemostasis in adipose tissue, subsequently enhancing ECM deposition and fibrosis [7,8,22][7][8][22].
Table 1. The main components in obesity-related ECM remodeling.
Component In Obesity In Cancer Function (In Obese) Ref.
Collagen VI Increased Increased Maintains 3D architecture; cellular function [14,40,46,47][14][37][38][39]
MMP14 Increased Increased Digests collagen; affects pre-adipocyte differentiation [33]
Fibronectin Increased Increased Structure support [34,61,62][34][40][41]
Elastin Decreased Increased Structure support [58][42]
Fibrillin-1 Increased Increased Forms microfibrils [64][43]
 

2.1. Collagen

Collagen is the major structural ECM component in adipose tissue. The increased expression and deposition of collagen I and collagen VI feature in obese and cancer-associated ECM remodeling [14,15,37,38,39][14][15][44][45][46]. Collagen I inhibits adipogenic differentiation via YAP activation whilst promoting myofibroblast differentiation in adipose tissue [37,38][44][45]. Collagen VI is highly expressed in adipocytes and its expression is significantly induced in adipose tissue during obese development [11]. Using a Col6α1−/− ob/ob mouse model [40][37], Dr. Philipp E. Scherer’s laboratory showed that a collagen VI deficiency led to an uncontrolled adipocyte expansion and was paradoxically associated with substantial improvements in whole-body energy homeostasis under high-fat diet exposure or in the ob/ob model [40][37]. Scientists have postulated that an absence of the ECM constrains adipocyte expansion to favor lipid storage over ectopic lipid accumulation [40,41][37][47]. The results from collagen VI (col6α1−/−)-deficient mice demonstrated that obesity-associated collagen deposition promoted mammary tumor progression [42,43,44][48][49][50]. One limitation of these studies was that the mouse model was not adipocyte-specific; a reduced collagen VI expression in other cell types and tissues may contribute to these phenotypes in knockout mice.
The role of collagen VI in obesity-related ECM remodeling has been extensively studied [11,31][11][31]. As a fibrillar collagen, collagen VI plays a pivotal structural role in obesity-related fibrosis. Collagen VI is composed of N-terminal globular sub-domains, collagenous regions, and C-terminal globular sub-domains [45][51]. In obese adipose tissue, the microfibrils formed by collagen VI assemble a highly filamentous meshwork through an interaction with other ECM molecules to maintain the three-dimensional tissue architecture [11,31,42][11][31][48].
Collagen VI is an important driver of fibroblast activation during fibrosis. ECM remodeling induced by collagen IV is associated with the activation of the TGF-β pathway. During obesity development, TGF-β is released and activated to induce SMAD2/3 phosphorylation [46][38]. The activation of the TGF-β pathway induces adipocyte de-differentiation and further enhances ECM deposition [46,47][38][39]. In addition, collagen VI expression in adipose tissue correlates with macrophage infiltration; notably, both collagen VI levels and a macrophage accumulation are associated with the body mass index [48][52]. Chronic inflammation featuring increased macrophage infiltration and excessive cytokine expression further modulates the ECM turnover and contributes to the progression of fibrosis in adipose tissue [49,50,51][53][54][55].
Endotrophin (ETP), a non-collagenous fragment of collagen VI, is an emerging biomarker for obesity. Bone morphogenetic protein 1 metalloproteinase and MMP14 have been identified as the proteases to cleave the α3 chain of collagen VI and generate ETP fragments [31,33][31][33]. Elevated ETP levels in plasma correlate with an aberrant matrix structure in adipose tissue that occurs during excessive fat storage [31]. The overexpression of ETP in obese mice further augmented insulin resistance, characterized by a significant increase in lipolysis, inflammation, and cellular apoptosis in adipose tissue [11]. Macrophage marker F4/80 and the acute-phase inflammatory marker serum amyloid A3 were significantly increased in ETP-transgenic mice under a high-fat diet (HFD) condition; an elevated ECM deposition was also observed in these mice. These results suggest that ETP triggers obesity-associated inflammation and fibrosis in adipose tissue [48][52]. ETP binds to TEM8/ANTXR1 and Neuron-glial antigen 2 (NG2) to induce AKT and WNT signaling in cancer cells, subsequently promoting mammary tumor progression [42,45][48][51]. These results demonstrate that the cleavage of collagen VI in adipose tissue induces metabolic changes and promotes obese phenotypes by elevating ETP levels. Adipocyte-derived ETP promoted malignant tumor progression in a mouse model [52,53][56][57]. ETP levels are elevated in human breast cancer and colon cancer patients [52,53][56][57]. These results suggest that ETP partially mediates obesity-associated tumor progression. ETP can also be derived from liver tissue [54][58]; therefore, it may contribute to liver-associated cancer progression.

2.2. MMPs

MMPs cleave many non-ECM proteins and also degrade different components of the ECM, essential for tissue homeostasis [55][59]. An alteration to the MMP expression or in the balance between MMPs and their tissue-specific inhibitors is crucial for ECM remodeling during normal tissue development and disease progression. During obese development, an increased expression of MMP3, MMP11, MMP12, MMP13, and MMP14 has been detected and a reduction in MMP7, MMP9, MMP16, and MMP24 has been detected [55,56,57][59][60][61]. MMP13 cleaves interstitial collagens such as type I and III. MMP3 and MMP7 are mainly involved in fibronectin degradation [55,56,57][59][60][61]. Among these MMPs, MMP14 (MT1-MMP1) is the predominant pericellular collagenase in adipose tissue [55][59].
MMP14 is highly expressed in obese adipose tissue [33]. Local hypoxia in obese adipose tissue drives the activation of HIF-1α, which further induces MMP14 expression [33]. A variant in the human MMP14 is linked to obesity and diabetes [58,59][42][62]. The silencing of MMP14 leads to an impaired adipose tissue formation; it eventually led to severe lipodystrophy in mice [55,58][42][59]. One important function of MMP14 in adipose tissue is to digest collagen VI and generate ETP [33]. At the early stage of obesity development, MMP14 digests collagen and prevents fibrosis, which in turn promotes the healthy expansion of the tissue [33]. At the late stage of obesity, tremendous amounts of collagen accumulate in adipose tissue [33]. The local pathological changes ultimately lead to systemic insulin resistance and other metabolic disorders [33]. The role of MMP14 in cancer development and progression has been well-established [60][63]. However, how obesity-associated MMP14 expression in adipose tissue contributes to cancer progression remains to be determined.

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