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 Updated on: Jan 9 2014

Proliferation and apoptosis

Proliferation and apoptosis: cell cycle, drug resistance mechanisms, angiogenesis

 

Subject
It is now recognised that myeloma cells need the microenvironment for their growth and survival and that specific abnormalities enable them to do so are involved in this process.

Firstly, the myeloma cells express various adhesion molecules that mediate extracellular matrix contact to normal stromal marrow fibroblasts. CD44 expression mediates binding to stroma and it regulates Interleukin-6 production, which is necessary for myeloma cell growth.

Secondly, expression of the Vascular Endothelial Growth Factor (VEGF) mediates the induction of angiogenesis, a process that creates the microenvironment for tumour growth.

 

Present Status
In the abnormal myeloma cells several specific translocations have been described that facilitate cell survival. t(4;14) involves expression of the Fibroblast Growth Factor Receptor 3 (FGFR3) in most cases, activation of which initiates intra cellular signalling and activation of anti-apoptotic genes in the myeloma cells. t(11;14) activates the cyclin D1 gene, which promotes the initiation of the cell cycle, enabling myeloma cells to divide and proliferate. Loss of tumour suppressor genes such as Retinoblastoma-1 gene through deletion of chromosome 13q, ongoing p53 mutations and activation of the proto-oncogenes c-Maf through the t(14;16) and C-myc, as well as activation of the anti-apoptosis genes bcl-2 and Mcl1 all result in improved survival advantages for abnormal myeloma cells.


The binding of PC to BM microenvironment is critical in the pathogenesis of MM, since it triggers the production of cytokines, promoting MM cell growth and survival, migration and the development of drug resistance. Soluble molecules (cytokines) that are found in BM microenvironment such as IL6, IGF-I, VEGF, TNFa, or SFD1a trigger Ras that in turn activate two different signal transduction pathways: 1) the Ras/Mek/MAPK route that induces proliferation of MM cells; and 2) the PI3K/Akt route which prevents apoptosis.

The concerted action of both routes favours expansion of the myelomatous clone acting on multiple downstream effectors, such as the NFkB that in turn regulates IL6 production. Another player of the PI3K/Akt route, the phosphatase PTEN has been shown to be mutated in MM resulting in increased resistance to apoptotic death. In addition, PC binding to fribronectin via b1 integrin receptors confers drug resistance throughout induction of a CAM-DR phenotype that is associated with the upregulation of p27 and FLIP-1 levels.


It has been shown in vitro that these mechanisms may be very important for the survival of myeloma cells through chemotherapy enabling these to develop new clones of tumour cells later on. In order to eradicate myeloma cells disruption of the close interaction of these cells with the microenvironment is required.

In addition, it has been shown that increase DNA repair is a common mechanism of tumour cell survival following treatment with alkylating agents such as melphalan, which is still the most used agent in multiple myeloma.


Preview of Programme Proposed
In this part of the program several laboratories will become partners, to unravel the mechanisms that enable myeloma cells to survive and proliferate in the bone marrow microenvironment and to avoid cell death from chemotherapy. We will define a common scientific goal for the combined efforts of all participants by;

  • prepare and distribute an overview of all available techniques and models in the participating laboratories
  • provide a list of assays and drugs that have been tested so far in current models, including non-published (negative) results
  • produce a list of potential mechanisms of drug insensitivity
  • to document and make available human myeloma samples characterized by specific translocations from each laboratory
  • to coordinate meetings aimed at initiating discussions on potential new targets for industion of apoptosis and reversal of drug resistance.

Deliverables and Cooperations
An integrated approach to find and to create synergism between these activities will enforce quality improvement of all programs. During the first 18 months we anticipate the following results;

  • the creation of a common activity bank in which the research program of each participating group is extensively described and accessible for all participants
  • the development of a common data bank of research hardware and software, indicating the facilities that each centre has available;
    secondly a full list of items which are used in the research programs, such as antibodies, probes, primers, sequences, cell lines, animal models, transgenic and knock-out models, clones etc.; the availability of these for other centres should be made clear and be a major goal of the integration
  • to establish bio-banks of myeloma samples
  • to describe the complementary expertise, which can be used in joint experiments between laboratories
  • to create an electronic database in which the results from high throughput approaches (genomics, proteomics) are made available.


Beyond 18 months the primary goal is to develop a coordinated strategy to define new mechanisms, which trigger myeloma proliferation, and to initiate a coordinated effort to perform a common research program between the participants in this area.

 

Links will be developed to stimulate "bench to bedside" developments and to feed relevant new information to the clinical trial groups. The participating groups/institutes will in the first place try to combine different questions, relating to each research program, in common cell/culture systems and models. Consequently, the research experiments from each group will have additional value. 

Secr. Hans E. Johnsen | Depart. of Haematology | Aalborg University Hospital | Sdr. Skovvej 15 | DK-9000 Aalborg | Denmark | T:+45 9766 3871 | F:+45 9766 6369