2 results
22 - BRAF mutations in human cancer: biologic and therapeutic implications
- from Part 2.1 - Molecular pathways underlying carcinogenesis: signal transduction
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- By Moriah H. Nissan, Human Oncology and Pathogenesis Program, and Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, David B. Solit, Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 272-277
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Summary
Introduction
The Mitogen-Activated Protein Kinase (MAPK or ERK) pathway is a central regulator of cellular proliferation and is frequently activated in human tumors. This pathway consists of the RAF, MEK (mitogen-activated protein kinase (MAPK) kinase) and ERK (extra-cellular signal-regulated kinase) kinases (see Figure 22.1). In normal cells, the RAS (K-, N-, and HRAS) small GTPase proteins activate the RAF kinases (ARAF, BRAF, and CRAF/RAF1) by regulating their cellular localization and homo- and heterodimerization (1). Recruitment of RAF to the plasma membrane by activated RAS induces an “open” conformation, which facilitates its phosphorylation and resulting kinase activation (2). Activation of RAF initiates a series of phosphorylation events, including the phosphorylation of the MEK1 and MEK2, and ERK1 and ERK2 kinases. Phosphorylated ERK in turn regulates several cellular processes such as cell-cycle progression and survival through phosphorylation of nuclear transcription factors and cytosolic proteins (3–8).
The ERK pathway operates as a negative feedback loop in which activation of the pathway is balanced by feedback regulatory elements including the dual-specificity phosphatases (DUSPs) and the Sprouty family proteins, the expression of which are ERK dependent (9,10). ERK pathway activity is also regulated by cross-talk with parallel signaling pathways such as the PI3K/AKT pathway and by scaffold proteins such as 14-3-3 that regulate RAF subcellular localization and stability (11).
29 - Testicular cancer
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- By David B. Solit, Memorial Sloan-Kettering Cancer Center, New York, Pamela N. Munster, Lee Moffitt Cancer Center Tampa
- Edited by Michael J. Fisch, University of Texas, M. D. Anderson Cancer Center, Eduardo Bruera, University of Texas, M. D. Anderson Cancer Center
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- Book:
- Handbook of Advanced Cancer Care
- Published online:
- 04 August 2010
- Print publication:
- 27 March 2003, pp 247-253
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Summary
Germ cell tumors (GCT) of the testis are the most common cancers of young men 15–35 years of age. Although relatively uncommon overall, their incidence has doubled over the past 40 years. Since the introduction of platinum-based combination regimens, the majority of patients with this disease are now cured.
Natural history
The majority (> 90%) of GCTs arise in the testis. Less common primary sites include the mediastinum, retroperitoneum, and the pineal/suprasellar region. Cryptorchism (the incomplete descent of one or both testes) is a well-defined risk factor for the development of this disease and the surgical correction of this problem (orchiopexy) performed prior to puberty reduces the risk for tumor development. Additional well-defined risk factors include a prior history of GCT and genetic syndromes including Klinefelter's and Down's syndromes.
Germ cell tumors can be divided by histologic type into seminomas (30%) and nonseminomatous germ cell tumors (NSGCT). Nonseminoma tumors may include any combination of the embryonal, endodermal sinus, choriocarcinoma, and teratoma histologies. A seminomatous component may also be present. The serum tumor markers human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) are often elevated in patients with either nonseminoma or seminoma, though elevated AFP is found only in patients with NSGCT and confirms the presence of a nonseminomatous component.
Pattern of spread and recurrence
The classic presentation of a testicular GCT is a painless scrotal mass though this finding occurs in only a minority of patients.