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Tuesday, October 7, 2014. The journal PLOS One
published an article on September 19 demonstrating BCM-95® curcumin
altered the microenvironment of a colorectal cancer cell culture model,
thereby reducing tumor promoting factors and potentially enhancing
chemotherapy effectiveness.
"Accumulating evidence suggests that the development and progression of
colorectal cancer is due to genetic and epigenetic alterations that are
the result of complex interactions of transformed cells with their
microenvironment," explain authors Constanze Buhrmann of Ludwig
Maximilian University in Germany and her colleagues. "The tumor
microenvironment is regarded as the tumor bed, which comprises of
resident components, such as stromal cells and the factors that are
stable within the milieu of the stroma, and nonresident components such
as different immune cell populations, which influence tumor invasion and
metastasis. The synergistic impact of the microenvironment on
inflammatory responses and tumor progression is now considered to be an
essential feature of carcinogenesis, and there is growing interest in
the identification of agents that specifically target the pathway
interaction between the tumor and stromal cells."
Dr Buhrmann and associates cultured human colon
cancer cells with human stromal fibroblast cells for three days. They
observed clustering of the cancer cells around the stromal cells, which
established close cell-to-cell contact. This cellular interaction was
associated with increased expression of adhesion and metastatic
molecules, active cell cycle proteins, transforming growth factor-beta3
(TGF-beta3) and vimentin, which is a marker of epithelial to mesenchymal
transition (EMT), a process that supports the initiation of metastasis.
The team then employed a three dimensional high
density tumor microenvironment in which colon cancer cells were
co-cultured with stromal cells and treated with varying concentrations
of BCM-95® curcumin and/or the chemotherapeutic drug 5-fluorouracil
(5-FU). While 5-FU alone increased tumor-promoting factors, TGF-beta3,
and EMT, pretreatment with curcumin prior to 5-FU administration reduced
these factors. Treatment with 5-FU and/or curcumin promoted
disintegration of high-density tumor spheres, an effect that was greater
in curcumin-treated co-cultures.
Cancer stem cells, which are believed to be
responsible for treatment resistance and tumor recurrence, were more
numerous in co-cultured cancer and stromal cells in comparison with
cancer cells alone, indicating the role of crosstalk in supporting in
tumor promotion. Administration of curcumin with or without 5-FU
inhibited and diminished the expression of cancer stem cell markers,
while 5-FU alone was associated with an increase—a fact that the authors
attribute to a defense reaction of the tumor cell culture and
microenvironment.
The results, according to the authors, demonstrate
"for the first time, the modulating effect of curcumin on the crosstalk
between the colorectal cancer cells/cancer stem cells and the
fibroblasts in the tumor microenvironment, creating an adequate climate
for more effective chemotherapeutic action of 5-FU to specifically
target chemoresistant colorectal cancer cells."
They conclude "that the natural NF-kB inhibitor
curcumin is a promising modulator of the synergistic crosstalk in the
tumor microenvironment and curcumin-based anti-EMT and tumor progression
may be a promising therapeutic strategy to prevent resistance to
chemotherapeutic agents, sensitizing cancer stem cells to 5-FU and
impede metastasis."
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