The oncogenes
Citations:
1) Murphy MJ, Wilson A, Trumpp A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 2005 Mar;15(3):128-37.
2) Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H. Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc. Oncogene. 2007 Mar 19; [Epub ahead of print]
3) Prendergast GC. Mechanisms of apoptosis by c-Myc. Oncogene. 1999 May 13;18(19):2967-87.
4) Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999 Jan;19(1):1-11.
5) Brooks DG, James RM, Patek CE, Williamson J, Arends MJ. Mutant K-ras enhances apoptosis in embryonic stem cells in combination with DNA damage and is associated with increased levels of p19(ARF). Oncogene. 2001 Apr 19;20(17):2144-52.
6) Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J. p53 suppresses the self-renewal of adult neural stem cells. Development. 2006 Jan;133(2):363-9.
7) Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005 Feb;7(2):165-71.
8) Li H, Cao Y, Berndt MC, Funder JW, Liu JP. Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro. Oncogene. 1999 Nov 18;18(48):6785-94.
9) Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006 Sep 28;443(7110):421-6.
The oncogene Myc plays a role in normal hematopoietic stem cells, activating stem cells to self-renew and differentiate (Murphy et al, 2005). c-Myc was also found to induce apoptosis and differentiation of human embryonic stem cells (Sumi et al, 2007). In a normal cell, c-Myc is able to induce apoptosis via Fas and TNF pathways, and is also connected to p19ARF and p53 mediated apoptosis (Prendergast, 1999). A number of other c-Myc targets are associated with cell growth and proliferation, like for instance, cyclin A and cyclin E (Dang, 1999).
The oncogene Ras is able to stimulate cell proliferation via the MAP kinase signalling pathway. However, Ras was also shown to be able to induce apoptosis in embryonic stem cells (Brooks et al, 2001) via the p19(ARF)-p53 route.
The tumor suppressors
The tumor suppressor p53 is able to induce apoptosis in the event of a DNA damage. A function for tumor suppressor p53 in stem cells has been elucidated, and it has been found that p53 is able to suppress self-renewal of adult neural stem cells (Meletis et al, 2006). It was also found that p53 could induce differentiation of mouse embryonic stem cells (Lin et al, 2005). In addition, it was also found that p53 could interact with telomerase in vitro (Li et al, 1999).
The tumor suppressor p16IN4A is a cell cycle inhibitor and it was found to reduce stem cell proliferation in older mice. It was also found that p16INK4A inhibition reduces aging in stem cells (Janzen, 2006).
The tumor suppressor, APC (adenamatous polyposis coli) was shown to be able to regulate embryonic stem cell survival, whereby it was shown that mutations in APC enhanced the survival of embryonic stem cells (Kim et al, 2004).
Telomeres and telomerase
It is known that stem cells do not have sufficient telomerase to prevent telomere shortening (Flores et al, 2006). It has also been suggested that telomerase activity may increase in later stages of carcinogenesis, as opposed to re-activation of the telomerase enzyme (Armanios & Greider, 2005). It was found that tumor suppressor p53 is able to downregulate the transcription of telomerase (Kanaya et al, 2000). It was also found that p53 was able to inhibit telomerase activity (Kusumoto et al, 1999). It was also found that p16INK4A could inhibit telomerase activity (Saito et al, 2004).
Developmental pathways and pathways within stem cells
The Wnt pathway is a developmental pathway, and it was subsequently shown to be involved in the self-renewal of hematopoietic stem cells (Reya et al, 2003). De-regulated Wnt signalling can occur as a result of APC mutations. The hedgehog pathway involving sonic hedgehog is another signalling pathway in stem cells (Bhardwaj et al, 2001). De-regulated hedgehog signaling can occur as a result of the absence of the Su(fu) protein, and somatic loss of functions mutations have also been found for Su(fu) (Sheng et al, 2004). It was also shown that Su(fu) has tumor suppressor properties (Meng et al, 2001).
Shown on my left are a list of possible mutational hits that leads to the transformation of a normal adult stem cell into a cancer stem cell.
Additions: Italicized text addition at the end of the paragraph to the section on Development pathways and pathways within stem cells. Diagram on left modified to add in Su(Fu) protein on Hedgehog pathway regulation.
Citations:
1) Murphy MJ, Wilson A, Trumpp A. More than just proliferation: Myc function in stem cells. Trends Cell Biol. 2005 Mar;15(3):128-37.
2) Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H. Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc. Oncogene. 2007 Mar 19; [Epub ahead of print]
3) Prendergast GC. Mechanisms of apoptosis by c-Myc. Oncogene. 1999 May 13;18(19):2967-87.
4) Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999 Jan;19(1):1-11.
5) Brooks DG, James RM, Patek CE, Williamson J, Arends MJ. Mutant K-ras enhances apoptosis in embryonic stem cells in combination with DNA damage and is associated with increased levels of p19(ARF). Oncogene. 2001 Apr 19;20(17):2144-52.
6) Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J. p53 suppresses the self-renewal of adult neural stem cells. Development. 2006 Jan;133(2):363-9.
7) Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2005 Feb;7(2):165-71.
8) Li H, Cao Y, Berndt MC, Funder JW, Liu JP. Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro. Oncogene. 1999 Nov 18;18(48):6785-94.
9) Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006 Sep 28;443(7110):421-6.
10) Kim KM, Calabrese P, Tavare S, Shibata D. Enhanced stem cell survival in familial adenomatous polyposis. Am J Pathol. 2004 Apr;164(4):1369-77.
11) Flores I, Benetti R, Blasco MA. Telomerase regulation and stem cell behaviour. Curr Opin Cell Biol. 2006 Jun;18(3):254-60.
12) M. ARMANIOS * AND C.W. GREIDER. Telomerase and Cancer Stem Cells. Cold Spring Harbor Symposia on Quantitative Biology 2005, Symposium 70, Pages 205-208.
13) Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H, Inoue M. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin Cancer Res. 2000 Apr;6(4):1239-47.
14) Kusumoto M, Ogawa T, Mizumoto K, Ueno H, Niiyama H, Sato N, Nakamura M, Tanaka M. Adenovirus-mediated p53 gene transduction inhibits telomerase activity independent of its effects on cell cycle arrest and apoptosis in human pancreatic cancer cells. Clin Cancer Res. 1999 Aug;5(8):2140-7.
15) Saito M, Nakagawa K, Hamada K, Hirose S, Harada H, Kohno S, Nagato S, Ohnishi T. Introduction of p16INK4a inhibits telomerase activity through transcriptional suppression of human telomerase reverse transcriptase expression in human gliomas. Int J Oncol. 2004 May;24(5):1213-20.
16) Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003 May 22;423(6938):409-14.
17) Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2001 Feb;2(2):172-80.
18) Sheng T, Li C, Zhang X, Chi S, He N, Chen K, McCormick F, Gatalica Z, Xie J. Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer. 2004 Oct 13;3:29.
5 comments:
Hi I have been studying the Hedgehog (Hh) pathway in its implications on cancer.
The hedgehog pathway is activated in a variety of cancers. Most cancers have properties of stem cells (they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types). However, with cancer they typically don’t specialize into certain cell type rather they stay poorly differentiated.
Cancer has been linked to various repair pathways such as hedgehog, notch, and wnt. These pathways in a simplified way of thinking get stuck on and continue proliferating in a state of continual repair.
The hedgehog pathway helps the cancer survive by activating other pathways to help it survive. It turns on pathways that tell the cell to divide, grow new bloods vessels around the tumor (angiogenic factors), and also prevent it for being detected by the immune system. When the body repairs itself it uses all of these properties to facilitate repair the problem arises when the repair properties are unregulated.
The hope with modulating this pathway when it is unregulated by the body is to turn it off with a inhibitor or Hedgehog Antagonist. This will turn off the hedgehog pathway and in turn modulate a number of other various properties of cancer cells allowing the cell to stop dividing and making it detectable to the immune system.
Here is a quote from a recent article
"Cancer stem cells or self-renewing cells in tumors Most cancer cells divide rapidly and many cancer cell lines can be grown indefinitely in culture as immortal cells, just as can embryonic stem cells. Embryonic carcinomas and teratocarcinomas are tumors derived from embryonic cells capable of differentiating into cells of many lineages. Beatrice Mintz and Ralph Brinster independently demonstrated that teratocarcinomas could give rise to normal chimeric mice (Mintz and Illmensee, 1975; Brinster, 1976), documenting the potential totipotentiality of some tumor cells. In 1994, the presence of cancerous stem cells in acute lymphocytic leukemia was documented by cloning such cells and documenting their self-renewing capacity
(Lapidot et al., 1994). A self-renewing cell population (cancer stem cells) have been identified in solid tumors such as breast and brain (Al-Hajj et al., 2003; Hemmati et al., 2003). These cancer stem cells represent approximately 1% of the
tumor and are the only cells in the tumor generating tumors into nude mice. Additional studies have also demonstrated the presence of a minor population of cells in cell lines with some of the same properties as stem cells (Hirschmann-Jax et al., 2004; Kondo et al., 2004). Many researchers now suspect that all cancers are composed of a mixture of stem cells and proliferative cells with a limited lifespan (Al-Hajj and Clarke, 2004; Dean et al., 2005).
The implications of this research are potentially far
reaching. The remission of many cancers following
therapy could be the result of the survival of the cancer
stem cells. Therefore, it is critical to fully characterize
these cells and to develop approaches to eliminate these
cells without excessive toxicity to normal stem cells.
Several important questions remain to be answered
concerning cancer stem cells. Do the side population
cells isolated from cell lines (Hirschmann-Jax et al.,
2004; Kondo et al., 2004) bear a relationship to cancer
stem cells? One unique property of cancer cells is the
ability, like normal stem cells, to grow in soft agar
cultures (Hamburger and Salmon, 1977). Only a
fraction of cells in a tumor cell culture can form a
colony in soft agar. Are the cells forming soft agar
colonies cancer stem cells? Again, a cell forming a
colony in soft agar must have self-renewal activity. Soft
agar assays could be renewed for the screening of drugs.
The vast majority of cancer fatalities are due to
metastasis – the spread of the initial tumor to other sites.
Stem cells, particularly the cells of the neural crest,
normally migrate (invade) throughout the developing
embryo. The neural crest gives rise to the precursors of
many metastatic cancers including melanoma, neuroblastoma
and small-cell lung tumors. Is the metastatic
ability of tumor cells an innate property of the cancer
stem cells? If so then the characterization of germ cell
migration could reveal new insights into metastasis.
Anticancer stem cell therapies could be effective at the
suppression of metastasis, resulting in substantial
increases in survival of the patient.
Targeted therapy for cancer stem cells: the patched pathway and
ABC transporters
H Lou and M Dean
Oncogene (2007) 26, 1357–1360
& 2007 Nature Publishing Group All rights reserved 0950-9232/07"
I would strongly urge you to read this article.
Tissue repair and stem cell renewal in carcinogenesis..
hedgehog@pathway2curis.com
Dear Anonymous:
Thanks very much for taking the time to read what I have posted.
First and foremost, the hedgehog pathway, like the Wnt and notch are running in normal stem cells I worked on the Wnt and notch pathways for my Honors thesis. However, I do not rule out a cross talk with the Hedgehog pathway, just that I didn't have time to finish that component. I worked on colorectal cancer and there have been studies indicating a crosstalk between Wnt and hedgehog pathways.
van den Brink GR, Hardwick JC. Hedgehog Wnteraction in colorectal cancer. Gut. 2006 Jul;55(7):912-4.
As an afterthought, whether the hedgehog antagonist can work depends on type of activation of the Hedgehog pathway. If the downstream effectors beyond the receptor is already constitutively active, it wouldn't be that effective to antagonize the receptor.
Dear Anonymous:
Thanks for your highlight of the Hedgehog pathway. I found a paper that studies the activation of the Hedgehog pathway, the Su(Fu) protein.
Current Hh antagonists (that target the SMO protein, which is more like a router of the pathway, you can target its receptor ptch but probably not the way it will be targeted in the clinic) will probably have no effect on cancer cells with mutations in the protein Su(Fu).
I can't stress enough that this pathway is probably the cause for metastasis in cancers. Because of this a large pharmaceutical giant is already in phase I trials for metastatic cancers. See regulation of Snail/ECadherin proteins and the Hh pathway.
With regards to the x-talk between Wnt and its sister pathway Hh, it seems to be a couple of kinases and maybe a nuclear shuttle or two. Su(Fu) also interacts with the Wnt pathway
Suppressor of fused negatively regulates beta-catenin signaling..
Cheers
Dear Anonymous:
Thanks for the paper. I think other than Hedgehog antagonists, Wnt antagonists are being researched on.
As an afterthought, cadherins do suppress the Wnt pathway as the former can sequester beta-catenin.
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