July 16, 2003
Penn Researchers Identify Secondary
Pathway for Survival of Cancer Cells
Discovery may lead to targeted therapies to interrupt cancer development
(Philadelphia, PA) - Researchers
at the Abramson Family Cancer Research Institute at
the University of Pennsylvania have determined that
a key enzyme, Pim-2, is responsible for the survival
of cancer cells. The finding - which will appear in
the August 1 edition of the journal Genes & Development
- represents an important advance in understanding why
cancer cells survive in the body (working against the
body's natural immune system), before growing into tumors.
It also answers a 20-year-old question as to the purpose
of Pim-2, an enzyme present in high concentrations in
many tumors, but left unstudied to this time; and it
equates Pim-2 with another, more commonly studied survival
pathway, the Akt-enzyme pathway.
"This finding is important because it shows, for the
first time, how Pim-2 works and its key role in cancer
cell survival," said Craig
Thompson, MD, Principal Investigator of the study
and Scientific Director of the Abramson Family Cancer
Research Institute (AFCRI). "Up until now, predominant
thinking has looked to the Akt pathway as the primary
pathway for cancer cells. Now we know that Pim-2 plays
an equally important role - and it is as much of a cancer-promoting
gene, or oncogene, as Akt.
"Our next step is to try and manipulate the action
of Pim-2, so that we can interfere with the survival
of cancer cells," said Thompson. "Ultimately, the hope
is that this could lead to new, targeted therapies for
killing cancer cells before they turn into deadly tumors
that can spread elsewhere in the body."
Pim-2 was originally identified, in 1984, as a serine/threonine
kinase, one of several hundred principal oncogenes under
investigation for their role in cancer cell survival
and growth. Its mutated form has been observed in high
quantities in cases of prostate cancer, leukemia and
multiple myeloma. Close to 50 kinases are thought to
play a key role in cancer progression.
Through a process of elimination, scientists test each
oncogene for its role or function in cancer progression,
manipulating each gene, to see which changes, called
mutations, allow the cell to live, and which ones let
the cell die. In the presence of Pim-2, sixty per cent
of cancer cells survived attempts to starve or kill
the cell. Cancer cells survived for the maximum duration
in the study - up to three weeks - with Pim-2 present,
regardless of whether or not growth factor (food for
the cell) was present. Only when both the Akt pathway
and Pim-2 pathway were dysregulated (no longer functioning
inside the cell), were cancerous cells unable to survive
and died. The Akt pathway is well studied because it
plays many roles in cancer progression, including a
key role in cancer cell survival.
Both Pim-2 and Akt survival pathways were found to
operate independently; Pim-2 was not activated by any
of the Akt pathway regulating enzymes - PI3K, HSP-90
and TOR. While Akt interacts with other enzymes to promote
cell survival, the function of Pim-2 is independent,
with no other enzymes required. The pathways were shown
to be distinct by their response to the antibiotic rapamycin:
Akt is sensitive to rapamycin and Pim-2 is not. Rapamycin
is a commonly used drug for treatment of transplant
patients, it restrains the body's immune response from
rejecting foreign growths, such as a new organ. Pim-2
overcomes this potent inhibitor of cell survival.
While these pathways appeared distinct, they are not
completely different and both have some common actions.
One factor shared by both pathways is a phosphorylated
"off signal" suppressor protein called 4E-BP1. Suppressor
genes prevent the cancer cell from growing, so when
turned "off", the cell can grow.
Exposing the role of Pim-2 was accomplished through
the latest technology for cancer research, a micro-array
analysis of RNA in the immune systems of mice.
Penn scientists focused their research on the question
of why cancer cells survive - and not simply removed
from the body by the immune system. For tumor cells
to grow, they must have the ability to ignore "death
signals" that would cause them to die, and not promote
cancer. Pim-2 had been shown as an important gene in
causing tumors in mouse experiments, and was also present
in large amounts in tumors. Over-production of Pim-2
allows the cells to ignore or become insensitive to
boosters of the immune system, such as the antibiotic
rapamycin.
The study took two years to complete (mid-2000 to mid-2002).
Funding was provided through grants from the National
Cancer Institute and the AFCRI.
RELATED
IMAGES
 Principal
investigator Craig Thompson, MD (right), shows immunologist
Casey Fox, PhD, images of gel results (dark bands) of
surviving cancer cells when enzyme Pim-2 is present.
Their latest research into the origins of cancer is
published in the August 1 edition of Genes & Development.
Abramson Family Cancer Research Institute, University
of Pennsylvania (2003) For larger
image, click here.
Principal investigator Craig Thompson,
MD (center), with fellow immunologist Casey Fox, PhD
(front right), and MD/PhD student Peter Hammerman (back
left). Their latest work on the origins of cancer appears
in the August 1 edition of Genes & Development, and
links the survival of cancer cells to the presence of
enzyme Pim-2. Abramson Family Cancer Research Institute,
University of Pennsylvania (2003). For
larger image, click here.
# # #
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