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Matricellular proteins: a sticky affair with cancers.

Chong HC, Tan CK, Huang RL, Tan NS - J Oncol (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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fig2: 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.

Mentions: Tumor metastasis is a multistep process involving the acquisition of malignant cell phenotypes that allow cancer cells to leave the primary tumor site and form secondary metastases via blood circulation (Figure 1). Each of these steps involves the cointeraction and coevolution of the tumor and its microenvironment and is in part affected by the heterotypic interactions between the cancer cells and neighboring stromal cells [1]. The tumor microenvironment consists of a myriad of cellular components, such as the non-malignant stromal fibroblasts, and endothelial cells, and an ECM comprised of proteins with structural and regulatory functions, including collagen, fibronectin and matricellular proteins [1, 2]. Matricellular proteins are a group of structurally diverse, ECM-associated glycoproteins, that are secreted by tumor and neighboring stromal cells in the tumor microenvironment [3, 4]. They have regulatory roles, such as the modulation of cell-cell and cell-matrix interactions, but do not contribute significantly to the structure of the ECM [4]. These proteins facilitate and contribute to various aspects of cancer cell behavior and growth, such as epithelial-mesenchymal transition (EMT), angiogenesis, cell proliferation and survival, as well as motility and ECM degradation (Figure 1) [2]. Numerous studies have shown how their interactions with the various cellular components initiate downstream signaling events that culminate in the acquisition of various hallmarks of cancer (Figure 2) [5].


Matricellular proteins: a sticky affair with cancers.

Chong HC, Tan CK, Huang RL, Tan NS - J Oncol (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: 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.
Mentions: Tumor metastasis is a multistep process involving the acquisition of malignant cell phenotypes that allow cancer cells to leave the primary tumor site and form secondary metastases via blood circulation (Figure 1). Each of these steps involves the cointeraction and coevolution of the tumor and its microenvironment and is in part affected by the heterotypic interactions between the cancer cells and neighboring stromal cells [1]. The tumor microenvironment consists of a myriad of cellular components, such as the non-malignant stromal fibroblasts, and endothelial cells, and an ECM comprised of proteins with structural and regulatory functions, including collagen, fibronectin and matricellular proteins [1, 2]. Matricellular proteins are a group of structurally diverse, ECM-associated glycoproteins, that are secreted by tumor and neighboring stromal cells in the tumor microenvironment [3, 4]. They have regulatory roles, such as the modulation of cell-cell and cell-matrix interactions, but do not contribute significantly to the structure of the ECM [4]. These proteins facilitate and contribute to various aspects of cancer cell behavior and growth, such as epithelial-mesenchymal transition (EMT), angiogenesis, cell proliferation and survival, as well as motility and ECM degradation (Figure 1) [2]. Numerous studies have shown how their interactions with the various cellular components initiate downstream signaling events that culminate in the acquisition of various hallmarks of cancer (Figure 2) [5].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.

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.

No MeSH data available.


Related in: MedlinePlus