Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012:2012:351089.
doi: 10.1155/2012/351089. Epub 2012 Feb 9.

Matricellular proteins: a sticky affair with cancers

Han Chung Chong  1 , Chek Kun Tan, Royston-Luke Huang, Nguan Soon Tan
Affiliations

Matricellular proteins: a sticky affair with cancers

Han Chung Chong et al. J Oncol. 2012.

Abstract

The multistep process of metastasis is a major hallmark of cancer progression involving the cointeraction and coevolution of the tumor and its microenvironment. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins, which are a family of nonstructural proteins in the extracellular matrix (ECM) that exert regulatory roles via a variety of molecular mechanisms. Matricellular proteins provide signals that support tumorigenic activities characteristic of the metastastic cascade such as epithelial-to-mesenchymal (EMT) transition, angiogenesis, tumor cell motility, proliferation, invasion, evasion from immune surveillance, and survival of anoikis. Herein, we review the current understanding of the following matricellular proteins and highlight their pivotal and multifacted roles in metastatic progression: angiopoietin-like protein 4 (ANGPTL4), CCN family members cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) and CCN6, osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), tenascin C (TNC), and thrombospondin-1 and -2 (TSP1, TSP2). Insights into the signaling mechanisms resulting from the interaction of these matricellular proteins and their respective molecular partner(s), as well as their subsequent contribution to tumor metastasis, are discussed. In addition, emerging evidences of their promising potential as therapeutic options and/or targets in the treatment of cancer are also highlighted.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Summarized the signaling mechanisms of various matricellular proteins contributing to cancer progression. ANGPTL4 binds to both integrins and ECM to promote tumor survival, tumor invasion and modulate the availability of ECM. (a) ANGPTL4 interacting with integrin activates Rac1 and NADPH oxidase, which generate high level of O2 −. This will further activating the Src machinery and stimulates its downstream PI3K/PKB mediated survival pathway. (b) ANGPTL4 interacting with integrin also activates FAK-src-PAK1 signaling and PKC/14-3-3 mediated pathway which modulate cell migration via integrin internalization. (c) ANGPTL4 binds specific matrix proteins and delays their degradation by proteases. However, this association does not interfere with integrin-matrix protein recognition unlike TNC. (d) TNC can compete with fibronectin to bind integrin α5β1 coreceptor, syndecan-4, which blocks the activation of promigratory FAK/RhoA/ROCK signaling pathway. (e) TNC can activate Wnt signaling by downregulating the soluble inhibitor DKK-1, thus resulted in nuclear localization of β-catenin. Nuclear β-catenin interacts with TCF/LEF to promote the expression of genes contributing to tumor formation, survival, and metastasis. OPN can interact with several (f) integrins and also (g) CD44 family of receptors. These complexes are able to mediate tumor cell survival through PI3k/PKB pathway activation and motility for detachment or invasion of tumor cell through the activation of AP-1-dependent gene expression via the MEK/Erk pathway. (h) Certain domains of TSP1 (such as NoC1) can bind directly to integrins to activate signaling proteins such as Erk1/2 and paxillin which modulates tumor formation. (i) TSP1 binding to CD36 activates Fyn and p38 MAPK pathway which is essential for the suppression of tumor growth. (j) TSP1 can also bind CD47, to modulate sGC and cGMP-dependent protein kinase, thus inhibiting the NO signaling necessary for angiogenesis. (k) TSP-1 association with CD47 or direct competitive binding of TSP1 to VEGF can inhibit VEGFR2 signaling. VEGFR2 activates the PI3K/PKB pathway which leads to activation of eNOS/NO signaling. Simultaneously, VEGFR2 can also signal through PLCγ, which further increases AMPK-mediated eNOS phosphorylation and NO production. eNOS/NO signaling regulate downstream targets that increase endothelial cell proliferation, migration, survival, and permeability. (l) TSP1 can activate TGFβ/smad pathway to inhibit tumor cell proliferation and induce apoptosis. (m) SPARC binds integrin, inducing ILK/FAK/PKB activation to increase cell migration. (n) Cyr61 can promote tumor cell proliferation and survival through the activation of integrin mediated signaling pathway either by direct binding with integrin or integrin-syndecan4. The downstream intracellular events may be mediated through the FAK/PI3K/PKB signaling pathway, resulting in either activation of the NF-κB survival pathway or phosphorylation of GSK3β and nuclear translocation of β-catenin for cell proliferation. (o) Cyr61 allows protein degradation of E-cadherin leading to β-catenin translocation.
Figure 2
Figure 2
Schematic illustration of cancer progression from primary tumor to metastasizing cancer and the involvement of various matricellular proteins in each process. Aberrant expression of matricellular proteins in tumors or in the surrounding stromal cells induces or inhibits the following tumorigenic and cancer progression events. (a) Epithelial-to-mesenchymal transition allows a normal epithelial cell, which normally adheres to basement membrane, to undergo a series of cellular and biochemical changes (i.e., a switch from E-cadherin to N-cadherin and increased vimentin expression) to adopt a mesenchymal phenotype. (b) Promotion of cell proliferation and survival in tumor cells lead to uncontrolled tumor growth. (c) Secretion of matrix metalloproteinases by tumor cells and acquisition of tumor cell motility result in basement membrane degradation and the increased invasiveness of the tumor cells. (d) Intravasation of invasive cancer cells through the basal membrane and endothelial monolayer allows the cancer cells to invade into the circulation. (e) Diminished immune surveillance and leukocyte recruitment against the circulating cancer cells permit the cells to survive in the circulation. (f) Matricellular proteins also promote resistance against anoikis and chemotherapy in order for the cancer cells to survive in the circulation. (g) Interactions of the matricellular proteins secreted by cancer cells with the surface receptors on endothelial cells result in an intermediate cell adhesion that allows the cancer cells to dock on the endothelial monolayer. (h) Adhered cancer cells subsequently undergo trans-endothelial migration through a process called extravasation to invade a distant site. (i) Establishment of new tumors at the metastatic site is dependent on the proliferation of invaded cancer cells; (j) Neovascularization within the tumor mass via angiogenesis is crucial for tumors to grow beyond a certain size. (+) and (−) denote positive and negative effects, respectively, imposed by the indicated matricellular proteins on the selected events. The disparate functions of any given matricellular proteins are dependent on the cell-type context and the specific structural domains that are expressed.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nature Reviews Cancer. 2009;9(4):239–252. - PMC - PubMed
    1. Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer and Metastasis Reviews. 2010;29(2):295–307. - PubMed
    1. Bornstein P. Matricellular proteins: an overview. Journal of Cell Communication and Signaling. 2009;3(3-4):163–165. - PMC - PubMed
    1. Bornstein P. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. Journal of Cell Biology. 1995;130(3):503–506. - PMC - PubMed
    1. Murphy-Ullrich JE. The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? Journal of Clinical Investigation. 2001;107(7):785–790. - PMC - PubMed