Expression and regulation of hedgehog signaling pathway in pancreatic cancer

Abstract

These results indicate that hedgehog signaling activation is a very common event in pancreatic cancer and that targeted inhibition of hedgehog signaling may be effective in treatment of pancreatic cancer.

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

“…In addition, an up-regulation of expression levels and/or activities of Hh signaling elements, including Hh ligands, SMO coreceptor, and GLI proteins often occurs during cancer initiation, and progression to locally invasive and metastatic disease stages. The overexpression of Hh signaling elements might result in the sustained growth and enhanced invasive properties of malignant cells in multiple myeloma, melanoma, glioma, gastrointestinal tract, pancreatic, hepatic, small-cell lung, prostate, mammary, and ovarian cancers (Thayer et al, 2003;Beachy et al, 2004;Karhadkar et al, 2004;Oniscu et al, 2004;Sanchez et al, 2004;Sheng et al, 2004;Ohta et al, 2005;Douard et al, 2006;Mimeault et al, 2006Mimeault et al, , 2007aBar et al, 2007;Bian et al, 2007;Chen et al, 2007b;Ehtesham et al, 2007;Peacock et al, 2007;Stecca et al, 2007;Bhattacharya et al, 2008;Liao et al, 2009;Mizuarai et al, 2009;Schnidar et al, 2009;Yang et al, 2010). More particularly, the reactivation of the Hh pathway and other developmental cascades, including EGFR and Wnt/␤-catenin, in tissue-resident adult stem/progenitor cells during severe tissue injury, chronic inflammation, and intense stress along chronological aging might promote the cancer initiation and development Nielsen et al, 2008;Batra, 2009, 2010a,c;Strobel et al, 2010).…”

“…These chemical compounds include the natural plant-derived steroidal alkaloid cyclopamine and its derivatives, such as 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl) cyclopamine (KAAD-cyclopamine), and semisynthetic D-homo-ring analogs IPI-269609 (Feldmann et al, 2008) and IPI-926 (Olive et al, 2009) as well as small synthetic molecules such as 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide (GDC-0049; HhAntag691), a proline derivative Cur61414 (Rubin and de Sauvage, 2006), and N-(6-((2S,6R) (Table 1) (Williams et al, 2003;Romer et al, 2004;Mimeault et al, 2006;Riobo et al, 2006a;Rubin and de Sauvage, 2006;Bar et al, 2007;Chen et al, 2007b;Clement et al, 2007;Lauth et al, 2007;Peacock et al, 2007;Stecca et al, 2007;Feldmann et al, 2008;Bü ttner et al, 2009;Eichenmü ller et al, 2009;Jimeno et al, 2009;Olive et al, 2009;Robarge et al, 2009;Tremblay et al, 2009;Mimeault and Batra, 2010b;Pan et al, 2010;Stanton and Peng, 2010;Yang et al, 2010). Moreover, small synthetic structural analogs of the second and third intracellular loops of the SMO proteins, such as small palmitoylated peptides as short as 10 residues, have also been designed (Remsberg et al, 2007).…”

“…Numerous studies have shown that the genetic and/or epigenetic alterations leading to the enhanced expression levels and/or activities of Hh signaling elements in stem/progenitor cells commonly occur in a wide variety of human cancers during etiopathogenesis and disease progression to locally invasive and metastatic stages (Berman et al, 2003;Cohen, 2003;Beachy et al, 2004;Rubin and de Sauvage, 2006;Taniguchi et al, 2007;Bhattacharya et al, 2008;Mimeault and Batra, 2008a;Tada et al, 2008;Varjosalo and Taipale, 2008;Schnidar et al, 2009;Yang et al, 2010;Mimeault and Batra, 2010c). Human cancer types frequently harboring a deregulation in the Hh pathway include leukemia, multiple myeloma, and brain, skin, head and neck, lung, liver, gastrointestinal, colorectal, pancreatic, prostate, mammary, ovarian, and renal carcinomas (Berman et al, 2003;Thayer et al, 2003;Karhadkar et al, 2004;Oniscu et al, 2004;Sanchez et al, 2004;Sheng et al, 2004;Ohta et al, 2005;Datta and Datta, 2006;Douard et al, 2006;Mimeault et al, 2006Mimeault et al, , 2007aBian et al, 2007;Chen et al, 2007b;Stecca et al, 2007;Taniguchi et al, 2007;Bhattacharya et al, 2008;Hegde et al, 2008;Tada et al, 2008;Eichenmü ller et al, 2009).…”

Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the Hedgehog signaling pathway

“…Proteins of the Hedgehog (Hh) signaling pathway, an important regulator of human embryonic development, are highly expressed in pancreatic cancer tissues or cells, and their expression appears to correlate to the occurrence, development and biological behavior of tumor cells (4). Hh signaling activation is a common event in pancreatic cancer (5). The Hh protein functions by binding to a 12-transmembrane domain receptor called patched 1 (Ptch1).…”

Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis

“…Aberrant activation of the Hh signaling pathway correlates with a variety of human tumors where the pathway is implicated in tumorigenesis, malignancy, metastasis and cancer stem cells (10)(11)(12)(13). Our previous study identified that activation of this pathway was a key event in the histogenesis of pancreatic cancer (14). In a transgenic mouse model of pancreatic cancer, inhibition of the Hh signaling pathway was found to reduce tumor-associated stromal tissues and to ameliorate gemcitabine uptake in tumor cells (15).…”