Dynamic interplay between the collagen scaffold and tumor evolution
Introduction
Many of the processes that regulate tissue and organ development are hijacked in cancer [1]. For example, the epithelial migration and invasion occurring in mammary carcinomas are morphologically and molecularly similar to epithelial branching morphogenesis in mammary gland development [2, 3]. However, while epithelial invasion is stringently regulated in development, solid tumors display deregulated and persistent invasion. In both instances, the extracellular matrix (ECM) provides a physical scaffold for cell adhesion and migration, it influences tissue tension and it signals to cells through ECM receptors. Proteolysis of the ECM regulates cellular migration by modifying the structure of the ECM scaffold and by releasing ECM fragments with biological functions. ECM proteolysis is therefore tightly controlled in normal tissues but typically deregulated in tumors.
Collagens are major constituents of the ECM, representing as much as 30% of total mammalian protein mass ([4], see Box 1). Type I collagen is the main structural protein in the interstitial ECM [5]. Type IV collagen is a key component of the basement membrane (BM), which is found at the basal surface of epithelial and endothelial cells and is essential for tissue polarity [6]. Epithelial invasion in both branching morphogenesis and cancer requires that the cells must interact with these collagens. The BM is breached as both normal and transformed epithelial cells invade into the interstitial tissue. It is also compromised at the site of the vasculature by metastasizing cancer cells [7•].
Section snippets
The desmoplastic response in cancer
Fibrosis is an accumulation of ECM proteins, including type I collagen [8]. Organ fibrosis and cancer are associated, although the association may simply reflect collagen accumulation due to increased activity of inflammatory and tumorigenic factors such as TGF-β [9]. Nevertheless, many malignancies are associated with a strong fibrotic reaction, termed ‘desmoplasia’, which is characterized by an accumulation of fibrillar collagen types I and III and increased degradation of type IV collagen [10
Architectural changes of fibrillar collagen in cancer
The architecture of the collagen scaffolds in tumors is severely altered. Tumor-associated collagens are often linearized and crosslinked reflecting elevated deposition and significant posttranslational modification ([18, 19••] and Figure 1). This physical restructuring of interstitial collagen progressively stiffens the ECM which thereafter elicits diverse effects on cellular differentiation, gene expression, proliferation, survival and migration [20, 21••, 22, 23••]. These cellular effects
Collagen fibers as highways for migration
The collagen fibers surrounding the normal epithelial structures in soft tissues such as the mammary gland and lung are typically curly and anisotropic. However, following tumor initiation many of the fibers progressively thicken and linearize ([18, 19••], and Figure 1a). This linearization is most notable adjacent to the tumor vasculature and in areas with cancer cell invasion [18, 19••, 36]. Linearized fibers are stiffer than curly ones and the resulting increased ECM stiffness can
Proteolysis of collagen — effects on cancer beyond path generation
Although cells migrate along collagen fibers, collagen in tissues also represents a physical barrier against invasion [44]. Thus, collagen degradation by proteases, including cathepsins and MMPs, and uptake of the degraded collagen is important for cancer cell invasion [10, 45•, 46]. For many cells, proteolysis of types I and IV collagen is essential for migration through the ECM [7•, 45•, 47, 48, 49]. Proteolysis of the ECM generates pathways for cells to migrate through [50•, 51, 52••, 53].
Collagen as a regulator of response to therapy
Resistance to cancer therapy can be caused by cancer cell intrinsic mechanisms, such as overexpression of anti-apoptotic genes, but factors in the tumor microenvironment can also regulate therapy response [1].
Types I and IV collagen can induce chemoresistance by directly interacting with integrins on cancer cells [70, 71••]. The level and structural organization of collagen can also indirectly influence therapeutic efficacy by regulating drug delivery. In many tumors, drug delivery is impaired
Interactions between collagen and the tumor immune infiltrate
A variety of immune cells are present in tumors and many of these accumulate and migrate within regions of dense fibrillar collagen [36, 38, 82]. How might the dense fibrillar collagen influence the function of immune cells? ECM stiffness promotes integrin-mediated adhesion assembly [21••], which could influence, for example, T cell activation. Another possibility is via collagen-mediated activation of leukocyte-associated Ig-like receptors (LAIRs). LAIRs are highly expressed on most immune
Collagen and regulation of differentiation
Matrix stiffness can determine stem cell lineage specification and direct mesenchymal stem cell differentiation into bone, neurons or muscle cells [92]. During bone development, inhibition of MMP-mediated cleavage of type I collagen leads to osteopenia, a loose bone structure, rather than increased bone formation [93], suggesting that an abnormal collagen scaffold modifies the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. Indeed, the collagenolytic activity of MMP-14
The challenges ahead
The overall architecture of the ECM is affected by collagen concentration, posttranslational modification (e.g. crosslinking) and proteolysis. In cancer, all of these levels of collagen metabolism are deregulated, resulting in an abnormal ECM architecture. However, to determine how this influences tumor evolution is challenging.
The study of the effects of collagen architecture on tumor evolution using in vitro assays has been informative, but a major concern is the ability to accurately
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Dr. Mark Sternlicht for his contribution to Figure 1. This work was supported by NIH grants U01CA141451 to ME and U54CA143836 and CA138818-01A1 to VMW and DOD grant W81XWH-05-1-0330 to VMW, as well as funding from the Breast Cancer Alliance, the Susan G Komen for the Cure, and Long Island 2 Day Walk to Fight Breast Cancer to ME. MGR was supported by Rigshospitalet, Augustinus fonden, Dagmar Marshalls fond, and the European Association for Cancer Research (EACR).
References (107)
- et al.
The tumor as an organ: complex tissues that interface with the entire organism
Dev Cell
(2010) - et al.
Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis
Dev Cell
(2008) - et al.
Collagens, modifying enzymes and their mutations in humans, flies and worms
Trends Genet
(2004) - et al.
Breaching the basement membrane: who, when and how?
Trends Cell Biol
(2008) - et al.
Three-dimensional context regulation of metastasis
Clin Exp Metastasis
(2009) - et al.
ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix
J Cell Biol
(2003) - et al.
Pdcd4 repression of lysyl oxidase inhibits hypoxia-induced breast cancer cell invasion
Oncogene
(2010) - et al.
Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo
Cancer Res
(2003) - et al.
Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma
Dis Model Mech
(2010) - et al.
Intravital imaging of cell movement in tumours
Nat Rev Cancer
(2003)
Discoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development
Mol Cell Biol
New functions for the matrix metalloproteinases in cancer progression
Nat Rev Cancer
Collagen degradation and platelet-derived growth factor stimulate the migration of vascular smooth muscle cells
J Cell Sci
Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen
Blood
Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin
Cancer Cell
Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon
J Biol Chem
Imaging intratumoral convection: pressure-dependent enhancement in chemotherapeutic delivery to solid tumors
Clin Cancer Res
Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector
Cancer Res
Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation
Nat Med
Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake
J Clin Invest
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer
Science
A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation
Nat Med
Stromal effects on mammary gland development and breast cancer
Science
Fibrillar collagen: the key to vertebrate evolution? A tale of molecular incest
Bioessays
Basement membranes: structure, assembly and role in tumour angiogenesis
Nat Rev Cancer
Inflammation and EMT: an alliance towards organ fibrosis and cancer progression
EMBO Mol Med
Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing
EMBO Rep
A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion
PLoS One
Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms
Cancer
Aberrant type I and type III collagen gene expression in human breast cancer in vivo
J Pathol
Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study
Mod Pathol
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Nature
Endogenous human microRNAs that suppress breast cancer metastasis
Nature
A molecular signature of metastasis in primary solid tumors
Nat Genet
Collagen reorganization at the tumor-stromal interface facilitates local invasion
BMC Med
Matrix crosslinking forces tumor progression by enhancing integrin signaling
Cell
The tension mounts: mechanics meets morphogenesis and malignancy
J Mammary Gland Biol Neoplasia
Tensional homeostasis and the malignant phenotype
Cancer Cell
A pericellular collagenase directs the 3-dimensional development of white adipose tissue
Cell
Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma
Am J Pathol
Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche
Cancer Cell
Lysyl oxidase is essential for hypoxia-induced metastasis
Nature
Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1
J Biol Chem
Fibronectin forms the most extensible biological fibers displaying switchable force-exposed cryptic binding sites
Proc Natl Acad Sci U S A
Mechanically activated integrin switch controls alpha5beta1 function
Science
Extracellular glycation crosslinks: prospects for removal
Rejuvenation Res
Protein glycation and oxidative stress in diabetes mellitus and ageing
Free Radic Biol Med
Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults
Am J Epidemiol
Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis
Proc Natl Acad Sci U S A
Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors
Cancer Res
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