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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