- A research team
has found that epigenetic changes are associated with certain forms of
pancreatic cancer that are known to spread to other organs like lung and
- Metastatic cancer
consume more glucose than local tumors
dehydrogenase enzyme fuelled metastasis
6-aminonicotinamide reversed the epigenetic changes
Study on DNA changes
in Pancreatic Cancer
research team comprising of scientists from various centers has found that a
complete genome analysis of tumor samples from people who died of pancreatic cancer
with certain chemical changes in the DNA. These changes did not alter the
sequence but they influenced how the DNA functions along with the survival
advantages that occurred in certain types of pancreatic cancer. These
advantages aided the cancer cells in surviving in organs like the lungs and the
liver, where there is ample supply of blood. The study was published in the
journal Nature Genetics.
Drug to Reverse the
drug that is still in the experimental stage has been found to reverse these
epigenetic changes and was found to block the growth of tumor in pancreatic
cancer cell lines. The scientists hope that such studies will aid in providing
an effective treatment against the development of metastatic pancreatic cancer.
‘The development of safe drugs that inhibit the enzyme 6-phosphogluconate dehydrogenase could lead to metastatic Pancreatic Cancer remission’
Andrew Feinberg who is a Bloomberg Distinguished Professor at The Johns Hopkins
University specializing in epigenetics, apart from being a member at Johns
Hopkins Kimmel Cancer Center, said that the findings of the study "astonished"
them. The changes that were caused to the regulation of the genes but not in
the sequence of the DNA were the driving forces that resulted in the successful
metastasis. The researchers claim that this is the first genome wide
experimental evidence to explain this phenomenon.
samples from 8 patients with pancreatic ductal adenocarcinoma, which is the
most common form of cancer, was collected soon after the death of these
patients. The samples were collected form the primary source of tumor, which
was in the pancreas or at a site close to the pancreas.
Analysis of the Tumor
genetic mutations in the tumor genomes analyzed to identify the genetic
mutations, or changes in the DNA. In an associated study, the researchers
reported that they did not find any genetic mutations which were linked
directly linked were responsible for the metastases.
there were no genetic alterations hat were identified, the team of researchers
looked for other changes that could possibly influence the spread of the tumor
cells. The research group looked for epigenetic changes that altered the
expression levels of various genes, thereby playing a role in the working of
the DNA. A combination of stains that were found in the patient tissues as well
as the examination of proteins that bind DNA along with whole genome sequencing
were studied to identify epigenetic changes and where they were located.
were no major changes that were noticed among cancer patients who had local
tumor, but there were major epigenetic changes identified among pancreatic cancer
patients who showed metastasis with spread to the lung and liver.
of the study authors Dr. Lacobuzio-Donahue said that the metastasizing cancer
moved, relatively, over longer distances and across blood vessels to reach a
good spot where they could colonize. However, in cancer that is localized, the
cancer cells stay close to the primary tumor
group of researchers identified block-like segments in which there were
epigenetic changes and these changes could be universal and could include
different types of cancers. The researchers state that though this idea hasn't
yet been tested, there are similar epigenetic changes in similar regions have
been identified in other types of cancer.
research team tried to identify what controlled the epigenetic changes. They
found that in cancer metastasis, the cells targeted organs that were sugar
rich, this lead the researchers to tumor cells had altered the way the tumor
cells use basic forms of sugar.
tests showed that tumors that metastasized consumed a lot more sugar than
tumors that were localized. They found that
cancers promoted growth via the metabolic reaction called the pentose
- This pathway aids
in burning or oxidizing glucose-derived molecules and converting them into
building blocks for tumors.
- The enzyme
6-phosphogluconate dehydrogenase (PGD) was found to be very important in
Rapid Growth of the
pancreatic cancer, it has always been found that the initial primary tumor
grows very slowly, taking a long time to develop. However, metastasizing cancer
progresses very fast and this has always been a mystery for researchers. The
alterations in the utilization of glucose, the researchers believe, could be
the answer behind this difference.
scientists needed to ascertain if PGD and the pentose phosphate pathway did
play a significant role in cancer metastasis and this was carried out by using
a drug that would inhibit PGD. The drug 6-aminonicotinamide (6AN), that
inhibits the action of PGD but is currently not used in humans as it is known
to cause side effects, was administered to cells showing metastasizing cancer.
This drug was found to reverse the epigenetic changes that were identified in
cells showing metastasis.
was found to
- Decrease the
activity of genes that were associated with malignant functions, which
included cell cycle control and DNA repair.
- The drug strongly
blocked the formation of tumor in distant metastases and this was reported
from three different laboratories.
researchers note with caution that further studies need to be conducted to find
out how the pentose phosphate pathway gets turned on and if there are any other
factors that could influence this pathway.
The study provides
clues to the important of the pentose phosphate pathway and, though further
research is required, it could provide better drug targets for therapy of
pancreatic cancer, especially for forms that lead to aggressive metastasis