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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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Role of mechanical forces and transforming growth factor β (TGFβ) in tumor desmoplasia and vessel compression. (A) TGFβ and mechanical forces contribute to the conversion of fibroblasts to contractile myofibroblasts. Myofibroblast formation results in upregulation of extracellular matrix (ECM) proteins and leads to tumor fibrosis, matrix stiffening and desmoplasia. Increased stiffening of the matrix, in turn, increases the magnitude of the mechanical forces and contributes to further activation of TGFβ from the ECM. This creates a positive feedback loop, which gives rise to a continuous activation of TGFβ and formation of myofibroblasts. (B) Upregulation of ECM proteins and the resulting increase in mechanical forces can compress and eventually collapse intratumoral blood vessels. Alleviation of these forces with an anti-TGFβ agent has the potential to decompress vessels and thus, improve perfusion and drug delivery to solid tumors [adapted with permission from (157)].
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f2-ijo-46-03-0933: Role of mechanical forces and transforming growth factor β (TGFβ) in tumor desmoplasia and vessel compression. (A) TGFβ and mechanical forces contribute to the conversion of fibroblasts to contractile myofibroblasts. Myofibroblast formation results in upregulation of extracellular matrix (ECM) proteins and leads to tumor fibrosis, matrix stiffening and desmoplasia. Increased stiffening of the matrix, in turn, increases the magnitude of the mechanical forces and contributes to further activation of TGFβ from the ECM. This creates a positive feedback loop, which gives rise to a continuous activation of TGFβ and formation of myofibroblasts. (B) Upregulation of ECM proteins and the resulting increase in mechanical forces can compress and eventually collapse intratumoral blood vessels. Alleviation of these forces with an anti-TGFβ agent has the potential to decompress vessels and thus, improve perfusion and drug delivery to solid tumors [adapted with permission from (157)].

Mentions: Tumor fibrotic response stiffens the tumor tissue, and as a result, it increases the compressive physical forces in the interior of the tumor (157). Compression of cancer cells alters their gene expression profile to enhance their invasive and metastatic phenotype (158,159). Furthermore, as mentioned previously, matrix stiffening along with the high contractile forces of myofibroblasts, cause further liberation of TGFβ from the LLC. These events suggest a positive feedback loop between TGFβ activation, myofibroblast contraction and ECM remodeling and production (Fig. 2A) (148). Finally, compression of intratumoral blood vessels reduces tumor perfusion, and thus, the delivery of oxygen (160). Hypo-perfusion and hypoxia, in turn contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies including radiation treatment and systemic administration of chemo- and nanotherapy (161–163).


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

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

Role of mechanical forces and transforming growth factor β (TGFβ) in tumor desmoplasia and vessel compression. (A) TGFβ and mechanical forces contribute to the conversion of fibroblasts to contractile myofibroblasts. Myofibroblast formation results in upregulation of extracellular matrix (ECM) proteins and leads to tumor fibrosis, matrix stiffening and desmoplasia. Increased stiffening of the matrix, in turn, increases the magnitude of the mechanical forces and contributes to further activation of TGFβ from the ECM. This creates a positive feedback loop, which gives rise to a continuous activation of TGFβ and formation of myofibroblasts. (B) Upregulation of ECM proteins and the resulting increase in mechanical forces can compress and eventually collapse intratumoral blood vessels. Alleviation of these forces with an anti-TGFβ agent has the potential to decompress vessels and thus, improve perfusion and drug delivery to solid tumors [adapted with permission from (157)].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ijo-46-03-0933: Role of mechanical forces and transforming growth factor β (TGFβ) in tumor desmoplasia and vessel compression. (A) TGFβ and mechanical forces contribute to the conversion of fibroblasts to contractile myofibroblasts. Myofibroblast formation results in upregulation of extracellular matrix (ECM) proteins and leads to tumor fibrosis, matrix stiffening and desmoplasia. Increased stiffening of the matrix, in turn, increases the magnitude of the mechanical forces and contributes to further activation of TGFβ from the ECM. This creates a positive feedback loop, which gives rise to a continuous activation of TGFβ and formation of myofibroblasts. (B) Upregulation of ECM proteins and the resulting increase in mechanical forces can compress and eventually collapse intratumoral blood vessels. Alleviation of these forces with an anti-TGFβ agent has the potential to decompress vessels and thus, improve perfusion and drug delivery to solid tumors [adapted with permission from (157)].
Mentions: Tumor fibrotic response stiffens the tumor tissue, and as a result, it increases the compressive physical forces in the interior of the tumor (157). Compression of cancer cells alters their gene expression profile to enhance their invasive and metastatic phenotype (158,159). Furthermore, as mentioned previously, matrix stiffening along with the high contractile forces of myofibroblasts, cause further liberation of TGFβ from the LLC. These events suggest a positive feedback loop between TGFβ activation, myofibroblast contraction and ECM remodeling and production (Fig. 2A) (148). Finally, compression of intratumoral blood vessels reduces tumor perfusion, and thus, the delivery of oxygen (160). Hypo-perfusion and hypoxia, in turn contribute to immune-evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies including radiation treatment and systemic administration of chemo- and nanotherapy (161–163).

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