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TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis.

Papageorgis P - J Oncol (2015)

Bottom Line: Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues.In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis.These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, Program in Biological Sciences, European University Cyprus, 6 Diogenes Street, Engomi, 1516 Nicosia, Cyprus.

ABSTRACT
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

No MeSH data available.


Related in: MedlinePlus

TGFβ signaling in epithelial-to-mesenchymal transition. TGFβ signaling mediated by Smad or non-Smad pathways can directly or indirectly induce the expression of different transcriptional “master regulators” of epithelial-to-mesenchymal transition. These factors, including Snail, Slug, ZEB1/delta EF1, and ZEB2/SIP1 are able to initiate a coordinated transcriptional network which results in suppression of epithelial and upregulation mesenchymal marker expression. As a result, epithelial cancer cells undergo dissolution of adherens and tight junctions along with dramatic remodeling of their cytoskeleton and acquire mesenchymal features. These fibroblast-like, spindle shaped tumor cells exhibit significantly enhanced migratory and invasive potential which allows them to enter the blood circulation through the basement membrane and initiate their metastatic dissemination to distal organs.
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Related In: Results  -  Collection


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fig2: TGFβ signaling in epithelial-to-mesenchymal transition. TGFβ signaling mediated by Smad or non-Smad pathways can directly or indirectly induce the expression of different transcriptional “master regulators” of epithelial-to-mesenchymal transition. These factors, including Snail, Slug, ZEB1/delta EF1, and ZEB2/SIP1 are able to initiate a coordinated transcriptional network which results in suppression of epithelial and upregulation mesenchymal marker expression. As a result, epithelial cancer cells undergo dissolution of adherens and tight junctions along with dramatic remodeling of their cytoskeleton and acquire mesenchymal features. These fibroblast-like, spindle shaped tumor cells exhibit significantly enhanced migratory and invasive potential which allows them to enter the blood circulation through the basement membrane and initiate their metastatic dissemination to distal organs.

Mentions: EMT is a vital process for morphogenesis during embryonic development and was initially appreciated primarily by developmental biologists. During the last decade, however, it has become apparent that EMT can be abnormally reactivated in adult tissues during pathological conditions such as cancer and fibrosis [165]. EMT involves the induction of an orchestrated, reversible transcriptional program in which well-organized, tightly connected epithelial cells transdifferentiate into disorganized and motile mesenchymal cells. This process is characterized by disruption of tight junctions between epithelial cells due to downregulation and delocalization of tight junction proteins zonula occludens 1 (ZO-1), occludin, and claudins. Similarly, adherens cell junction complexes containing E-cadherin, p120, γ-catenin, and β-catenin also undergo dissolution. This is followed by loss of apical-basal cell polarity, dramatic remodeling of the cytoskeleton, and the formation of actin stress fibers. Concomitantly, cells acquire mesenchymal features such as spindle-shaped, fibroblast-like morphology and express mesenchymal components including N-cadherin, vimentin, fibronectin, and alpha smooth-muscle actin [166, 167]. TGFβ signaling plays an instrumental role in activating this transcriptional network by inducing the expression of several pleiotropically acting transcription factors, also known as “master regulators” of EMT. TGFβ-induced factors include the Snail family of proteins Snail [168] and Slug [169] as well as the two-handed zinc finger factors ZEB1/deltaEF1 [170] and ZEB2/SIP1 [171] while the basic helix-loop-helix (bHLH) protein Twist [172] can be upregulated by Wnt, EGFR, or STAT3 signaling [173, 174]. Other EMT transcription factors, also induced by the TGFβ-Smad pathway, such as HMGA2 [175] or Ets1 [176], act as upstream regulators in this network by upregulating the expression of Snail and ZEB family members, respectively. On the other hand, FOXC2 is a factor which functions downstream of Snail and Twist to promote EMT (Figure 2) [177]. In addition to these transcriptional mechanisms, recent studies indicate that overactive TGFβ-Smad2 signaling further contributes to the establishment of an EMT phenotype bymaintaining the epigenetic silencing of key epithelial marker genes, such as E-cadherin, claudin-4, kallikrein-10, and cingulin. This appears to be mediated via Smad2-dependent regulation of DNA methyltransferase 1 (DNMT1) binding activity and DNA methylation of the corresponding gene promoter regions [71].


TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis.

Papageorgis P - J Oncol (2015)

TGFβ signaling in epithelial-to-mesenchymal transition. TGFβ signaling mediated by Smad or non-Smad pathways can directly or indirectly induce the expression of different transcriptional “master regulators” of epithelial-to-mesenchymal transition. These factors, including Snail, Slug, ZEB1/delta EF1, and ZEB2/SIP1 are able to initiate a coordinated transcriptional network which results in suppression of epithelial and upregulation mesenchymal marker expression. As a result, epithelial cancer cells undergo dissolution of adherens and tight junctions along with dramatic remodeling of their cytoskeleton and acquire mesenchymal features. These fibroblast-like, spindle shaped tumor cells exhibit significantly enhanced migratory and invasive potential which allows them to enter the blood circulation through the basement membrane and initiate their metastatic dissemination to distal organs.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4389829&req=5

fig2: TGFβ signaling in epithelial-to-mesenchymal transition. TGFβ signaling mediated by Smad or non-Smad pathways can directly or indirectly induce the expression of different transcriptional “master regulators” of epithelial-to-mesenchymal transition. These factors, including Snail, Slug, ZEB1/delta EF1, and ZEB2/SIP1 are able to initiate a coordinated transcriptional network which results in suppression of epithelial and upregulation mesenchymal marker expression. As a result, epithelial cancer cells undergo dissolution of adherens and tight junctions along with dramatic remodeling of their cytoskeleton and acquire mesenchymal features. These fibroblast-like, spindle shaped tumor cells exhibit significantly enhanced migratory and invasive potential which allows them to enter the blood circulation through the basement membrane and initiate their metastatic dissemination to distal organs.
Mentions: EMT is a vital process for morphogenesis during embryonic development and was initially appreciated primarily by developmental biologists. During the last decade, however, it has become apparent that EMT can be abnormally reactivated in adult tissues during pathological conditions such as cancer and fibrosis [165]. EMT involves the induction of an orchestrated, reversible transcriptional program in which well-organized, tightly connected epithelial cells transdifferentiate into disorganized and motile mesenchymal cells. This process is characterized by disruption of tight junctions between epithelial cells due to downregulation and delocalization of tight junction proteins zonula occludens 1 (ZO-1), occludin, and claudins. Similarly, adherens cell junction complexes containing E-cadherin, p120, γ-catenin, and β-catenin also undergo dissolution. This is followed by loss of apical-basal cell polarity, dramatic remodeling of the cytoskeleton, and the formation of actin stress fibers. Concomitantly, cells acquire mesenchymal features such as spindle-shaped, fibroblast-like morphology and express mesenchymal components including N-cadherin, vimentin, fibronectin, and alpha smooth-muscle actin [166, 167]. TGFβ signaling plays an instrumental role in activating this transcriptional network by inducing the expression of several pleiotropically acting transcription factors, also known as “master regulators” of EMT. TGFβ-induced factors include the Snail family of proteins Snail [168] and Slug [169] as well as the two-handed zinc finger factors ZEB1/deltaEF1 [170] and ZEB2/SIP1 [171] while the basic helix-loop-helix (bHLH) protein Twist [172] can be upregulated by Wnt, EGFR, or STAT3 signaling [173, 174]. Other EMT transcription factors, also induced by the TGFβ-Smad pathway, such as HMGA2 [175] or Ets1 [176], act as upstream regulators in this network by upregulating the expression of Snail and ZEB family members, respectively. On the other hand, FOXC2 is a factor which functions downstream of Snail and Twist to promote EMT (Figure 2) [177]. In addition to these transcriptional mechanisms, recent studies indicate that overactive TGFβ-Smad2 signaling further contributes to the establishment of an EMT phenotype bymaintaining the epigenetic silencing of key epithelial marker genes, such as E-cadherin, claudin-4, kallikrein-10, and cingulin. This appears to be mediated via Smad2-dependent regulation of DNA methyltransferase 1 (DNMT1) binding activity and DNA methylation of the corresponding gene promoter regions [71].

Bottom Line: Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues.In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis.These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, Program in Biological Sciences, European University Cyprus, 6 Diogenes Street, Engomi, 1516 Nicosia, Cyprus.

ABSTRACT
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

No MeSH data available.


Related in: MedlinePlus