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Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review).

Papageorgis P, Stylianopoulos T - Int. J. Oncol. (2015)

Bottom Line: Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner.In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs.These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus.

ABSTRACT
Deregulation of cell signaling homeostasis is a predominant feature of cancer initiation and progression. Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner. Aberrant activity of TGFβ signaling is well known to play dual roles in cancer, depending on tumor stage and cellular context. The crucial roles of TGFβ in modulating the tumor microenvironment, its contribution to the accumulation of mechanical forces within the solid constituents of a tumor and its effects on the effective delivery of drugs are also becoming increasingly clear. In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs. We also report the implications of tumor mechanics in cancer therapy and the potential usage of anti‑TGFβ agents to enhance drug delivery and augment existing therapeutic approaches. These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.

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Related in: MedlinePlus

Smad-dependent and -independent transforming growth factor β (TGFβ) pathways. TGFβ is initially synthesized and stored in the extracellular matrix (ECM) in an inactive form, as part of the large latent complex (LLC). Upon activation, the released TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors (TGFβRs) exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated receptor-associated Smads can form a heterotrimeric complex with Smad4, which interacts with other co-factors in the nucleus to regulate the expression of TGFβ target genes. In addition, downstream intracellular signaling may also be transduced via auxiliary pathways including the MEK/Erk, the Rho-like GTPases, the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) and the p38/mitogen-activated protein kinase (MAPK) pathways to regulate biological responses such as epithelial-to-mesenchymal transition (EMT), cell adhesion, migration and survival.
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f1-ijo-46-03-0933: Smad-dependent and -independent transforming growth factor β (TGFβ) pathways. TGFβ is initially synthesized and stored in the extracellular matrix (ECM) in an inactive form, as part of the large latent complex (LLC). Upon activation, the released TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors (TGFβRs) exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated receptor-associated Smads can form a heterotrimeric complex with Smad4, which interacts with other co-factors in the nucleus to regulate the expression of TGFβ target genes. In addition, downstream intracellular signaling may also be transduced via auxiliary pathways including the MEK/Erk, the Rho-like GTPases, the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) and the p38/mitogen-activated protein kinase (MAPK) pathways to regulate biological responses such as epithelial-to-mesenchymal transition (EMT), cell adhesion, migration and survival.

Mentions: The TGFβ superfamily encompasses around 40 secreted cytokines, including TGFβ, bone morphogenetic proteins (BMPs), activins, nodal, lefty, myostatin, anti-Müllerian hormone (AMH) and growth differentiation factors (GDFs). These cytokines regulate a plethora of biological functions such as cell proliferation and apoptosis, embryonic patterning, stem cell maintenance, cell differentiation, migration and immune surveillance. Importantly, the effects of these factors are characterized as cell-type specific as well as context dependent (1–3). The TGFβ isoforms, with most common being TGFβ1, 2 and 3, are initially synthesized as 75 kDa inactive homodimers, known as pro-TGFβ, which consist of TGFβ associated with latency-associated proteins (LAPs) at the N-terminal part of the pro-peptide. This is part of the TGFβ large latent complex (LLC), comprised of the LAPs and the latency TGFβ-binding proteins (LTBPs) (4–7), and is covalently associated to the ECM via the N-terminal region of LTBPs (8,9) (Fig. 1). While TGFβ is part of the LLC complex, it remains in an inactive form since the high affinity association of LAPs with TGFβ prevents the interaction with its receptors (10). During TGFβ activation, LAPs undergo conformational changes induced by thrombospondin-1 (TSP-1) (11,12) followed by cleavage mediated by furin convertase, plasmin or matrix metalloproteinases MMP-2/9 resulting in the release of the mature 24 kDa TGFβ dimer (13–15). The active ligand is then able to bind and activate TGFβ receptors (TGFβRs) to propagate downstream intracellular signaling events. Therefore, the processing of pro-TGFβ into the active TGFβ ligand is a critical regulatory step which determines its bioavailability.


Role of TGFβ in regulation of the tumor microenvironment and drug delivery (review).

Papageorgis P, Stylianopoulos T - Int. J. Oncol. (2015)

Smad-dependent and -independent transforming growth factor β (TGFβ) pathways. TGFβ is initially synthesized and stored in the extracellular matrix (ECM) in an inactive form, as part of the large latent complex (LLC). Upon activation, the released TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors (TGFβRs) exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated receptor-associated Smads can form a heterotrimeric complex with Smad4, which interacts with other co-factors in the nucleus to regulate the expression of TGFβ target genes. In addition, downstream intracellular signaling may also be transduced via auxiliary pathways including the MEK/Erk, the Rho-like GTPases, the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) and the p38/mitogen-activated protein kinase (MAPK) pathways to regulate biological responses such as epithelial-to-mesenchymal transition (EMT), cell adhesion, migration and survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306018&req=5

f1-ijo-46-03-0933: Smad-dependent and -independent transforming growth factor β (TGFβ) pathways. TGFβ is initially synthesized and stored in the extracellular matrix (ECM) in an inactive form, as part of the large latent complex (LLC). Upon activation, the released TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors (TGFβRs) exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated receptor-associated Smads can form a heterotrimeric complex with Smad4, which interacts with other co-factors in the nucleus to regulate the expression of TGFβ target genes. In addition, downstream intracellular signaling may also be transduced via auxiliary pathways including the MEK/Erk, the Rho-like GTPases, the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) and the p38/mitogen-activated protein kinase (MAPK) pathways to regulate biological responses such as epithelial-to-mesenchymal transition (EMT), cell adhesion, migration and survival.
Mentions: The TGFβ superfamily encompasses around 40 secreted cytokines, including TGFβ, bone morphogenetic proteins (BMPs), activins, nodal, lefty, myostatin, anti-Müllerian hormone (AMH) and growth differentiation factors (GDFs). These cytokines regulate a plethora of biological functions such as cell proliferation and apoptosis, embryonic patterning, stem cell maintenance, cell differentiation, migration and immune surveillance. Importantly, the effects of these factors are characterized as cell-type specific as well as context dependent (1–3). The TGFβ isoforms, with most common being TGFβ1, 2 and 3, are initially synthesized as 75 kDa inactive homodimers, known as pro-TGFβ, which consist of TGFβ associated with latency-associated proteins (LAPs) at the N-terminal part of the pro-peptide. This is part of the TGFβ large latent complex (LLC), comprised of the LAPs and the latency TGFβ-binding proteins (LTBPs) (4–7), and is covalently associated to the ECM via the N-terminal region of LTBPs (8,9) (Fig. 1). While TGFβ is part of the LLC complex, it remains in an inactive form since the high affinity association of LAPs with TGFβ prevents the interaction with its receptors (10). During TGFβ activation, LAPs undergo conformational changes induced by thrombospondin-1 (TSP-1) (11,12) followed by cleavage mediated by furin convertase, plasmin or matrix metalloproteinases MMP-2/9 resulting in the release of the mature 24 kDa TGFβ dimer (13–15). The active ligand is then able to bind and activate TGFβ receptors (TGFβRs) to propagate downstream intracellular signaling events. Therefore, the processing of pro-TGFβ into the active TGFβ ligand is a critical regulatory step which determines its bioavailability.

Bottom Line: Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner.In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs.These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus.

ABSTRACT
Deregulation of cell signaling homeostasis is a predominant feature of cancer initiation and progression. Transforming growth factor β (TGFβ) is a pleiotropic cytokine, which regulates numerous biological processes of various tissues in an autocrine and paracrine manner. Aberrant activity of TGFβ signaling is well known to play dual roles in cancer, depending on tumor stage and cellular context. The crucial roles of TGFβ in modulating the tumor microenvironment, its contribution to the accumulation of mechanical forces within the solid constituents of a tumor and its effects on the effective delivery of drugs are also becoming increasingly clear. In this review, we discuss the latest advances in the efforts to unravel the effects of TGFβ signaling in various components of the tumor microenvironment and how these influence the generation of forces and the efficacy of drugs. We also report the implications of tumor mechanics in cancer therapy and the potential usage of anti‑TGFβ agents to enhance drug delivery and augment existing therapeutic approaches. These findings provide new insights towards the significance of targeting TGFβ pathway to enhance personalized tumor treatment.

Show MeSH
Related in: MedlinePlus