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MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions.

Chandhanayingyong C, Kim Y, Staples JR, Hahn C, Lee FY - Sarcoma (2012)

Bottom Line: In addition, most high-grade chondrosarcoma does not respond to current chemotherapy.With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities.Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Orthopedic Research (COR), Department of Orthopedic Surgery, Columbia University, New York, NY 10032, USA.

ABSTRACT
The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena.

No MeSH data available.


Related in: MedlinePlus

MAPK/ERK signaling and the hallmarks of cancers. The MAPK/ERK pathway mediates several upstream signals from well-known oncogenic growth factors and proinflammatory stimulants. Activation of the MAPK/ERK pathway by growth factors, proinflammatory stimulants and gain-of-function mutations of Ras/Raf promotes phenotypic changes characteristic of cancer cells [9–14].
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Related In: Results  -  Collection


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fig1: MAPK/ERK signaling and the hallmarks of cancers. The MAPK/ERK pathway mediates several upstream signals from well-known oncogenic growth factors and proinflammatory stimulants. Activation of the MAPK/ERK pathway by growth factors, proinflammatory stimulants and gain-of-function mutations of Ras/Raf promotes phenotypic changes characteristic of cancer cells [9–14].

Mentions: Extracellular Receptor Kinase (ERK) proteins are a family of protein-serine/threonine kinases that are activated via the phosphorylation of tyrosine in response to growth factors such as insulin and nerve growth factor (NGF). ERK is also known as the Mitogen-activated Protein Kinase (MAPK), and plays a major role in mediating inflammatory as well as oncogenic signals. MAPK is activated by MAPK/ERK Kinase (MEK). Ras/Raf is upstream of MEK. In the classical setting, MEK is activated by many upstream growth factors/cytokine receptors in response to radiation, hypoxia, physical forces, TNF, RANKL, and TLR. When gain-of-function mutations occur in Ras/Raf, a commonly observed phenomenon in many types of cancers, MEK/MAPK proteins become constitutively activated. MAPK/ERK signaling fulfills many cancer hallmarks by the mediation of mitosis and stem-cell-ness, production of matrix degrading enzymes, Warburg effect, angiogenesis, bone destruction, cytokine production, chromosomal aberration, and anergy [9–13] (Figure 1).


MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions.

Chandhanayingyong C, Kim Y, Staples JR, Hahn C, Lee FY - Sarcoma (2012)

MAPK/ERK signaling and the hallmarks of cancers. The MAPK/ERK pathway mediates several upstream signals from well-known oncogenic growth factors and proinflammatory stimulants. Activation of the MAPK/ERK pathway by growth factors, proinflammatory stimulants and gain-of-function mutations of Ras/Raf promotes phenotypic changes characteristic of cancer cells [9–14].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3345255&req=5

fig1: MAPK/ERK signaling and the hallmarks of cancers. The MAPK/ERK pathway mediates several upstream signals from well-known oncogenic growth factors and proinflammatory stimulants. Activation of the MAPK/ERK pathway by growth factors, proinflammatory stimulants and gain-of-function mutations of Ras/Raf promotes phenotypic changes characteristic of cancer cells [9–14].
Mentions: Extracellular Receptor Kinase (ERK) proteins are a family of protein-serine/threonine kinases that are activated via the phosphorylation of tyrosine in response to growth factors such as insulin and nerve growth factor (NGF). ERK is also known as the Mitogen-activated Protein Kinase (MAPK), and plays a major role in mediating inflammatory as well as oncogenic signals. MAPK is activated by MAPK/ERK Kinase (MEK). Ras/Raf is upstream of MEK. In the classical setting, MEK is activated by many upstream growth factors/cytokine receptors in response to radiation, hypoxia, physical forces, TNF, RANKL, and TLR. When gain-of-function mutations occur in Ras/Raf, a commonly observed phenomenon in many types of cancers, MEK/MAPK proteins become constitutively activated. MAPK/ERK signaling fulfills many cancer hallmarks by the mediation of mitosis and stem-cell-ness, production of matrix degrading enzymes, Warburg effect, angiogenesis, bone destruction, cytokine production, chromosomal aberration, and anergy [9–13] (Figure 1).

Bottom Line: In addition, most high-grade chondrosarcoma does not respond to current chemotherapy.With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities.Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Orthopedic Research (COR), Department of Orthopedic Surgery, Columbia University, New York, NY 10032, USA.

ABSTRACT
The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena.

No MeSH data available.


Related in: MedlinePlus