IntroductionMantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin lymphoma whose normal counterpart is likely represented by pre-germinal center, naive B cells that populates the mantle zone of lymph nodes. 1 MCL is characterized by advanced stage at presentation, frequent extranodal localization, and aggressive clinical behavior, with poor response to conventional therapeutic regimens and a very unfavorable prognosis, even when the disease is treated with high-dose therapy and autologous bone marrow transplantation. 1 More than 95% of MCLs show the t(11;14) (q13;q32) translocation, which results in a juxtaposition of the CCND1 gene locus to the immunoglobulin heavy chain promoter and the subsequent cyclin D1 overexpression, 1,2 leading to the deregulation of the cyclin D/Rb pathway. Cyclin D1 deregulation, however, is not sufficient for lymphomagenesis; cooperation with microenvironmental stimuli, such as IL-4, IL-10, and CD40 activation, as well as additional genetic changes, are probably required to induce and sustain the transformed phenotype of mantle cells. Indeed, defects involving inhibitors of G 1 cell-cycle progression, such as p53, p27 Kip1 , p16 INK4a , and p15 INK4 , may also occur in MCL. 3,4 More recently, gene-expression profiling and proteomic studies demonstrated that MCL cells carry a profound deregulation of multiple genes and pathways that are involved in the control of cell growth and survival. 5,6 Despite these advances, however, only limited information is available on the mechanisms responsible for the constitutive activation of critical signaling pathways and their functional significance. Elucidation of these issues is of particular relevance to identify and exploit tumor-specific molecular signatures for new treatment strategies.Among the signaling pathways that may be deregulated in MCL cells, the phosphatidyl-inositol-3 kinase (PI3-K)/Akt pathway has recently attracted great interest as a possible therapeutic target. The PI3-K pathway is activated by a wide range of tyrosine kinase growth factor receptors and is the major activator of Akt, a serine/threonine protein kinase that modulates the function of a variety of downstream substrates involved in the regulation of cell-cycle progression, differentiation, transcription, translation, cell survival, and angiogenesis. Activation of PI3-K generates the membrane lipid phosphatidylinositol-trisphosphate (PIP3), which favors the recruitment of Akt to the plasma membrane, where the Akt kinase is activated upon phosphorylation by 3-phosphoinositide-dependent protein kinase-1 (PDK-1). Akt activation is counteracted by PTEN, a lipid phosphatase that dephosphorylates PIP3, whose expression is lost in a variety of tumor cells. 7 Moreover, recent evidence also indicates that PTEN can be inactivated by phosphorylation of serine 380/threonine 382/383 on its carboxy-terminal regulatory domain. [8][9][10] Nevertheless, the role of phosphorylated PTEN in human tumors has been poorly investigated so far. Submitted July 26, 2007; accepted Marc...

BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process. PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR. RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (Po0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r ¼ À0.24, P ¼ 0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P ¼ 0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P ¼ 0.03). CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.