IGF and Cancer?

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    IGF and Cancer?


    I have been talking to someone about cycles, IGF, and growth hormone. This person will remain nameless just to make it easier. Anyways here is what he posted.

    "I would have to look it up again but i dont like the literature on
    injected igf and it causing cancer related problems, vs igf
    liberation from the liver with gh which doesnt seem to be as scary
    in that area----igf kind of scares me on that front"

    I was wondering if anyone else has read literature on this and could provide me with some insight.

    Thanks

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    IGF-1 strongly influences tumor cell migration and metastasis devlopment (primarily in cancers that metastasize to the liver). The effects of IGF-1 on existing cancer cells is well documented but as a carcinogen I think the role of IGF-1 remains relatively unknown.
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    So the problems is that if you have pre-existing cancer just starting to develop that you arte not aware of you could really decrease your chances of beating it if you kick in some IGF?
    Quote Originally Posted by canadian champ
    IGF-1 strongly influences tumor cell migration and metastasis devlopment (primarily in cancers that metastasize to the liver). The effects of IGF-1 on existing cancer cells is well documented but as a carcinogen I think the role of IGF-1 remains relatively unknown.
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    Quote Originally Posted by Mr.50
    So the problems is that if you have pre-existing cancer just starting to develop that you arte not aware of you could really decrease your chances of beating it if you kick in some IGF?
    I cant really answer that question because I dont think there is a feasible way to test this hypothesis (it would even be difficult for an animal model to work in this case). What I can tell you (in addition to what I have already mentioned) is that IGF-1 increases proliferation, migration, and invasion of many types of cancer cells in vitro. For a variety of other cancers, specific subuntis of the IGF-1 pathway are constitutively upregulated towards metastases.
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    What he said.

    It is a gamble using this stuff much in the same way it is using hormones. An existing tumor, with the proper oncology, might feed off of whatever endogenous hormone or peptide you are using. I personally do not feel that the compounds in question are themselves carcinogenic, but I have no data to prove or disprove this hypothesis.
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    Quote Originally Posted by bioman
    What he said.

    An existing tumor, with the proper oncology, might feed off of whatever endogenous hormone or peptide you are using. .
    In general, I would agree with your statement but keep in mind that most anaplastic cells are self-sufficient for growth signalling so additional growth signals may simply be redundant (as is the case in cancers where RAS and RAF are mutated and thus constitutively on).
    What I find particularily interesting are the recent studies suggesting that IGF-1 is crucial for creating the essential local environment for liver metastases to form.
    Sorry for getting off topic fellas.
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    "Sorry for getting off topic fellas.
    cc"

    Not at all. It's all related and therefore very interesting. We appreciate your input.
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    I would love to see these studies if anyone has them. I am a bit of a freak when it comes to getting hard info and just the thought of someone saying that it might help cancer survive or for that matter increase just seems a bit over the top. Not that you all are wrong because I would never say this what so ever, I just would like to see some more info on the subject.
    Thanks,

    Whale
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    Quote Originally Posted by whale
    I would love to see these studies if anyone has them. I am a bit of a freak when it comes to getting hard info and just the thought of someone saying that it might help cancer survive or for that matter increase just seems a bit over the top. Not that you all are wrong because I would never say this what so ever, I just would like to see some more info on the subject.
    Thanks,

    Whale
    Not a problem. I didnt say that it helped cancer survive, I said that it promoted cell invasion, migration, proliferation and that there is a role for this ligand (perhaps as a chemoattractant) in creating a local liver environment suitable for metastastic growth. These studies were done with a lab that i am currently involved in a collaboration with.

    Cancer Res. 2004 May 15;64(10):3380-5. Related Articles, Links


    Loss of tumorigenicity and metastatic potential in carcinoma cells expressing the extracellular domain of the type 1 insulin-like growth factor receptor.

    Samani AA, Chevet E, Fallavollita L, Galipeau J, Brodt P.

    Department of Medicine, McGill University Health Center, McGill University, Montreal, Quebec, Canada.

    The receptor for the type 1 insulin-like growth factor (IGF-IR) was identified as a major regulator of the malignant phenotype and a target for cancer therapy. In the present study, a novel IGF-IR mutant consisting of the entire extracellular domain of the receptor (IGFIR(933)) was genetically engineered and expressed in highly metastatic H-59 murine lung carcinoma cells. We show here that the cells expressed a truncated heterotetramer (beta(m)-alpha-alpha-beta(m)) that was secreted into the medium and could neutralize the effects of exogenous IGF-I, thus diminishing IGF-I-induced signaling and blocking IGF-I-mediated cellular functions such as cell proliferation, invasion, and survival. In vivo, tumor incidence and growth rate were markedly reduced in mice inoculated s.c. with H-59/IGFIR(933) cells. Moreover, after the intrasplenic/portal inoculation of these cells, there was a 90% reduction in the incidence of hepatic metastases and a significant increase in the long-term, disease-free survival of the mice compared with controls. Our results identify the IGFIR(933) as a potent antitumorigenic and antimetastatic agent with potential applications for cancer gene therapy.

    PMID: 15150088 [PubMed - indexed for MEDLINE]
    1: Horm Metab Res. 2003 Nov-Dec;35(11-12):802-8. Related Articles, Links


    The role of the IGF-I receptor in the regulation of matrix metalloproteinases, tumor invasion and metastasis.

    Zhang D, Samani AA, Brodt P.

    Department of Surgery, McGill University Health Center, the Royal Victoria Hospital, Montreal, Quebec, Canada.

    The breakdown of the extracellular matrix (ECM) by proteinases is an essential step in the process of cancer invasion and metastasis. Malignant progression is frequently associated with upregulated production and/or activity of one or several ECM degrading proteinases. Prominent among them are the matrix metalloproteinases (MMPs). The MMPs constitute a family of structurally related, zinc-dependent endopeptidases collectively capable of degrading essentially all the components of the extracellular matrix. At present, 23 members of the human MMP gene family are known. The increased expression and/or activity of one or more members of this family have been documented in essentially all human malignancies and some have been implicated in the process of angiogenesis. Prominent among those are MMP-2 and MT1-MMP, two metalloproteinases that form a cell membrane-associated complex leading to MMP-2 activation and ECM proteolysis. Here, we review our data that identified the type 1 insulin-like growth factor receptor (IGF-IR) as a regulator of tumor invasion and the synthesis of MT1-MMP and MMP-2 and report on the signal transduction pathways that mediate this regulation. These findings are discussed in the context of a broader review of the role of the IGF-IR/IGF axis in the regulation of tumor invasion and metastasis.

    Oncogene. 2003 Feb 20;22(7):974-82. Related Articles, Links


    Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling.

    Zhang D, Brodt P.

    Department of Surgery, McGill University Health Center, The Royal Victoria Hospital, Montreal, Quebec, Canada.

    The membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as a major activator of MMP-2 - a process involving the formation of a trimolecular complex with TIMP-2. We previously identified the IGF-I receptor as a positive regulator of MMP-2 synthesis. Here, we investigated the role of IGF-IR in the regulation of MT1-MMP. Highly invasive Lewis lung carcinoma subline H-59 cells express MT1-MMP and utilize it to activate their major extracellular matrix degrading proteinase-MMP-2. These cells were transiently transfected with a plasmid vector expressing a luciferase reporter gene downstream of the mouse MT1-MMP promoter. IGF-I treatment increased luciferase activity in the transfected cells by up to 10-fold and augmented endogenous MT1-MMP mRNA and protein synthesis by up to 2-3-fold, relative to controls. MT1-MMP induction and invasion were blocked by the PI 3-kinase inhibitors LY294002 and wortmannin and by rapamycin, but not by the MEK inhibitor PD98059. Overexpression of a dominant negative Akt mutant or of the tumor suppressor phosphatase and tensin homologue, PTEN, in these cells also caused a significant reduction in MT1-MMP expression and invasion. The results demonstrate that IGF-IR controls tumor cell invasion by coordinately regulating MMP-2 expression and its MT1-MMP-mediated activation and identify PI 3-kinase/Akt/mTOR signaling as critical to this regulation.


    This is a very interesting overview.
    Baserga R. Controlling IGF-receptor function: a possible strategy for tumor therapy. Trends Biotechnol, 14: 150-2, 1996.

    Hope this helps! Lots of information out there!
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    Quote Originally Posted by canadian champ
    In general, I would agree with your statement but keep in mind that most anaplastic cells are self-sufficient for growth signalling so additional growth signals may simply be redundant (as is the case in cancers where RAS and RAF are mutated and thus constitutively on).
    What I find particularily interesting are the recent studies suggesting that IGF-1 is crucial for creating the essential local environment for liver metastases to form.
    Sorry for getting off topic fellas.
    cc
    You are VERY on topic!!
    First off, Taking GH over IGF-1 to avoid cancer growth is pointless, in the end your dosing IGF-1 either way.

    It seems most cancer tumors produce their own IGF-1 and 2 within themselves. This can lead to hypoglycemia for no other reason then the tumer is jacking your nutrients.

    That being said, signifficiant research on IGF-1 supression is being done with great sucess.
    This seems to contridict each other,.. cancerous toumores produce their own, so why would supressing the bodies IGF limit growth?...
    Bottom line, if you dont have cancer, your fine. If you knowingly do,.. your just dumb
    If you do but ya dont know,.. an upside would be IF it causes it to become visiable, you'll detect it earlier,.. and the more rapid rate of increase may provide an excellerated rate of secondary symptoms,.. so you would know you had it,.. and the younger you are the easier it would be to recover from the cancer removal.
    Its always a risk.
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    Here is an interesting paper on how cancer moves around. Its not really IGF-1 related by may allay some of the fears that IGF-1 will cause movement of cancer.

    VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.

    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D.

    Department of Pediatrics and the Children's Blood Foundation Laboratories, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.

    The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the ar***** of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

    PMID: 16341007 [PubMed - indexed for MEDLINE]

    Basically it shows that before cancer moves, small "nests" of blood vessels and tissue are formed ahead of the metastasis. Blockage of these progenitor (think stem cell) cells receptor, VEGFR-1, or removal of cells that were VEGFR-1 positive, stopped metastasis in mice. So maybe you could use antibodies as part of your PCT so you wont have to worry about metastasis. Just kidding about the PCT but I had to tie all of this into IGF-1 somehow so as to stay on topic.
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    this is a great paper that was just published in nature. it also deals with local liver environment.... good posting, although i doubt anyone is going to juice with vascular endothelial growth factor haha. is a great paper though and offers insight into what i was talking about before.
    cc

    Quote Originally Posted by tedtickle
    Here is an interesting paper on how cancer moves around. Its not really IGF-1 related by may allay some of the fears that IGF-1 will cause movement of cancer.

    VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.

    Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D.

    Department of Pediatrics and the Children's Blood Foundation Laboratories, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.

    The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the ar***** of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

    PMID: 16341007 [PubMed - indexed for MEDLINE]

    Basically it shows that before cancer moves, small "nests" of blood vessels and tissue are formed ahead of the metastasis. Blockage of these progenitor (think stem cell) cells receptor, VEGFR-1, or removal of cells that were VEGFR-1 positive, stopped metastasis in mice. So maybe you could use antibodies as part of your PCT so you wont have to worry about metastasis. Just kidding about the PCT but I had to tie all of this into IGF-1 somehow so as to stay on topic.
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    IGF-1 is commonly used on animals. Obviously, they do not show increased cancer from it. That would be bad for business.

    Moreover, there was ever a difference between autocrine IGF-1 and paracrine IGF-1. Autocrine is the IGF-1 expressed internally by the cells themselves. This has effects that are different than those that happen when an IGF-1 molecule binds to the external surface (insulin?) receptor. Cancer cells overexpress (autocrine) IGF-1, this is widely known. As to the effects of an IGF-1 molecule attaching to the surface receptors of a cancerous cells, I have not seen any serious information as to what that does. But since IGF-1 is after all a "Growth" Factor, chances are that it helps the tumor grow.
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    Quote Originally Posted by Grunt76
    IGF-1 is commonly used on animals. Obviously, they do not show increased cancer from it. That would be bad for business.

    Moreover, there was ever a difference between autocrine IGF-1 and paracrine IGF-1. Autocrine is the IGF-1 expressed internally by the cells themselves. This has effects that are different than those that happen when an IGF-1 molecule binds to the external surface (insulin?) receptor. Cancer cells overexpress (autocrine) IGF-1, this is widely known. As to the effects of an IGF-1 molecule attaching to the surface receptors of a cancerous cells, I have not seen any serious information as to what that does. But since IGF-1 is after all a "Growth" Factor, chances are that it helps the tumor grow.
    Autocrine signalling still involves secretion of the ligand (IGF-1), it simply implies that the ligand acts only on the cell that secretes it. It must bind to the external receptor (IGFR1) in order for the signalling cascade to occur. Unless, of course, if a downstream component of the pathway is constitutively upregulated which is the case for some cancers in regards to IGF-1 and most certainly in many cancers that involve mutated ras/raf signalling pathways.
    In regards to your other point, if a cell has a wildtype IGFR1 receptor and IGF-1 comes into contact with it, the pathway will be activated. IGF-1 is IGF-1, regardless of the source (of same species of course and if they are wild-type). IGF-1 DEFINITELY binds to cancer surface cell receptors and acts as a mitogen. The cell extends pseudopodia towards IGF-1 (it is a chemokine) and MIGRATES towards the highest concentration. IGF-1 also operates in the MMP pathways which are essential for degrading the extra cellular matrix which is what permits a cell to leave a tumor and travel and perhaps form distant metastases (and we all know it is in fact the metastases that kill in most cancers). IGF-1 also triggers proliferation in cancer cells. In conclusion (haha) IGF-1 causes many types of cancer cells to PROLIFERATE, INVADE, and MIGRATE. IGF-1 is a very potent chemokine.
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