2008 Scientific Report

Van Andel Research Institute | Scientific Report
Role of androgen receptor in integrin-mediated survival
All primary and metastatic prostate cancers express the intracellular steroid receptor for androgen (AR). In the normal gland,
the AR-expressing cells do not interact with the ECM in the basement membrane; however, all AR-expressing tumor cells do
adhere to the ECM in the basement membrane. In normal cells, AR expression suppresses growth and promotes differentiation,
but in tumor cells AR expression promotes cell growth and is required for cell survival. The mechanisms that lead to
the change from growth inhibition and differentiation to growth promotion and survival are unknown. Our hypothesis is that
adhesion to the ECM by the tumor cells is responsible for driving the change in AR function by initiating crosstalk between AR
and integrins.
When prostate tumor cells are placed in culture, they lose expression of AR. The reason for this is not clear, but it may have
to do with loss of the appropriate ECM-containing basement membrane. When we introduce AR into prostate tumor cells, it
actually suppresses their growth and induces cell death. However, if we place the AR-expressing tumor cells on laminin (the
ECM found in tumors), these cells no longer die. We have determined that AR expression results in increased expression of
a6b1 integrin, the receptor for laminin. Thus, AR-expressing tumor cells are likely to survive better when they remain adherent
to the laminin-rich ECM that is present in the prostate gland. Survival under these conditions appears to depend on the
ability of AR to enhance expression of the laminin receptor, a6b1 integrin; we are currently determining how AR regulates the
expression of this integrin.
Role of CD82 and integrin signaling in prostate cancer metastasis
Death from prostate cancer is due to the development of metastatic disease, which is difficult to control. The mechanisms
involved in progression to metastatic disease are not understood. One approach we are taking is to characterize genes that
are specifically associated with metastatic prostate cancer. CD82/KAI1 is a metastasis suppressor gene whose expression
is specifically lost in metastatic cancer, but not in primary tumors. Interestingly, CD82/KAI1 is known to associate with both
integrins and RTKs. Our goal has been to determine how loss of CD82/KAI1 expression promotes metastasis by studying the
role of CD82/KAI1 in integrin and RTK crosstalk.
We have found that reexpression of CD82/KAI1 in metastatic tumor cells suppresses laminin-specific migration and invasion
via suppression of both integrin- and ligand-induced activation of the RTK c-Met. Interestingly, c-Met is often overexpressed in
metastatic prostate cancer. Thus, CD82/KAI1 normally acts to regulate signaling through c-Met such that upon CD82 loss in
tumor cells, signaling through c-Met is increased, leading to increased invasion. We are currently determining the mechanism
by which CD82/KAI1 down-regulates c-Met signaling. So far our investigations indicate that c-Met and CD82 do not directly
interact, and CD82 may act to suppress c-Met signaling indirectly by dispersing the c-Met aggregates on metastatic tumor cells
into monomers, thus blocking signaling. We are developing mutants of CD82 to determine which part of the CD82 molecule is
required for suppression of c-Met activity. In addition, we have determined that reexpression of CD82 in tumor cells induces a
physical association between CD82 and a related family member, CD9. Loss of CD9 prevents CD82 from suppressing c-Met.
We are currently determining whether CD82/CD9 association with integrins is required to suppress c-Met.
We have also initiated several mouse studies to demonstrate the importance of CD82 in regulating metastasis in vivo. Using
orthotopic injection of wild-type or CD82-expressing metastatic prostate tumor cells directly into the prostate, we found that
CD82 also suppresses metastasis in vivo. The ability of some prostate cancer cells to metastasize depends on activation of
c-Met. Using mice that are able to specifically activate c-Met, we have been able to demonstrate that these tumor cells will
only metastasize when c-Met is active. Under these conditions, reexpression of CD82 completely suppresses metastasis.
In addition, we have generated mice in which CD82 expression is specifically lost in the epithelial cells of the prostate gland.
These mice will be crossed to mice that develop only primary tumors to determine if the loss of CD82 is sufficient to induce
prostate cancer metastasis.
40