RECEPTOR TYROSINE KINASES AND CHEMOKINE RECEPTORS COOPERATE IN STIMULATING TUMORS METASTATIC BEHAVIO

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RECEPTOR TYROSINE KINASES AND CHEMOKINE RECEPTORS
COOPERATE IN STIMULATING TUMORS METASTATIC
BEHAVIOR

• Marcin Majka and Katarzyna Miekus
• Department of Transplantation
• Jagiellonian University Medical College
• Krakow, Poland

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Introduction

• Normal and pathological cell behavior (e.g.
  growth, faith, motility) is govern by various
  extracellular signals transmitted by cell surface
  receptors.
• Several families of surface receptors has been
  discovered. They transmit signals stimulating or
  inhibiting proliferation, apoptosis,
  differentiation.
• In physiological and pathological settings each
  cell constantly receives signals from several
  different receptors and these signals
  interconnect with each other.

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MET and CXCR4 receptors in tumor biology
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MET receptor tyrosine kinase

• MET receptor, encoded by MET proto-oncogene, has
  been shown to play a very important role in
  development and progression of various tumors.
• MET activity is a key event during tumor
  metastasis and MET overexpression and
  hyperactivation have been reported to correlate
  with metastatic ability of the tumor cells.

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Role of HGF-MET axis in tumor growth and
metastasis

• proliferation
• survival
• motility

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CXCR4 a G-protein coupled chemokine receptor

• CXCR4
• a receptor for stromal derived factor -1
  (SDF-1) expressed on e.g. HSC, lymphoid cells,
  endothelium and tumor cells (e.g. neuroblastoma,
  breast cancer, rhabdomyosarcoma, cervical
  carcinoma)
• SDF-1
• a chemokine, constitutively expressed in several
  tissues (e.g. lung, bone marrow) directs
  migration of normal and tumor cells

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Role of SDF-1-CXCR4 axis in tumor growth and
metastasis

• growth
• vascularization
• local spread
• metastasis

Burger JA and Kipps TJ Blood 2006
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Rhabdomyosarcoma

• Rhabdomyosarcoma (RMS) is the most common soft
  tissue sarcoma developing in children and
  adolescent
• For newly diagnosed RMS patients the long term
  prognosis is good. However, the survival rate of
  patients with metastasic disease is only 20

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The migratory ability of MET negative cells
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Reduction of CXCR4 expression and activation in
MET negative cells
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Inhibition of intracellular pathways
activation in MET negative cell lines
Rhabdomyosarcoma
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Downregulation of MET receptor blocks
angiogenesis in RMS cells
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RMS tumor growth is inhibited by MET receptor
downregulation

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MET negative cells undergo differentiation in
vivo
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Metastatic ability of RMS cell is reduced by MET
inhibition
ERMS
ARMS
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Cervical carcinoma

• Cervical carcinoma is a leading cause of deaths
  among women suffering from cancer
• Early-stage cervical cancer is curable in most
  patients
• In Poland about 4000 women are diagnosed with
  cervical cancer every year and the 5-year
  survival rate is one of the lowest in Europe

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Morphology of MET negative cervical carcinoma
cell line
WT
shLacZ
shMET
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(No Transcript)
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Reduced tumor growth of MET negative cervical
carcinoma cell line
weight of tumor g
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Histopathology study of tumors formed by control
and MET negative tumor cells
Hematoxylin/eosin-stained paraffin sections of
the tumors lesions
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Decreased expression of CXCR4 and migration
toward SDF-1 gradient by MET negative cervical
carcinoma cells
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Inhibition of intracellular pathways
activation in MET negative cervical cell lines
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Bone marrow appearance after HTB-35 cell line
injection
shLacZ
shMET
WT
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• Expression of MET and CXCR4 in
• differentiated RMS cells

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Pharmacological differentiation of RMS cells
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MET and CXCR4 expression and activation in
differentiated RMS cells
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Conclusions

• Inhibition of MET signaling decreases ability of
  rhabdomyosarcoma and cervical carcinoma to
  migrate and metastasise
• Expression and function of CXCR4 receptor in
  rhabdomyosarcoma and cervical carcinoma is
  closely related to the presence and activation of
  HGF-MET axis

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Conclusions

• Presence of MET receptor is responsible for
  keeping ARMS in less differentiated state
• Induction of rhabdomyosarcoma differentiation
  couses downregulation of MET and CXCR4 expression
  and reduced metastatic ability of rabdomyosarcoma
  cells in vitro and in vivo

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Conclusions

• Presence of one type of the receptor could be
  crucial to induce full activation of another type
  of the receptor

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Acknowledgments

• Department of Transplantation
• Ewa Lukasiewicz
• Jacek Kijowski
• Department of Clinical Immunology
• Grazyna Drabik
• Robert Miezynski
• Department of Cell Biology
• Zbigniew Madeja
• Ewa Wybieralska