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Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19 Podcast
Differentiation of mesenchymal stem cells from the adipose tissue into carcinoma-associated myofibroblasts in interaction with human breast cancer cells

Differentiation of mesenchymal stem cells from the adipose tissue into carcinoma-associated myofibroblasts in interaction with human breast cancer cells

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19 vor 12 Jahren

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Major advances in understanding and treating breast cancer have
been made in the last two decades, yet it remains a significant
problem with breast cancer being the most commonly identified
cancer and the leading cause of cancer death among women worldwide.
For many years breast cancer research has mainly focused on
genetically changed cancer cells. However, recently the importance
of the stromal compartment surrounding cancer cells in facilitating
tumor growth, invasion and metastasis has been widely recognized.
Cumulating evidence suggests that in particular
carcinoma-associated myofibroblasts play a key role within the
tumor stroma and influence many aspects of carcinogenesis.
Nevertheless, the cell type of origin as well as the precise
mechanisms by which these cells develop has not been conclusively
established and remains controversial. The role of human adipose
tissue derived stem cells (hASCs) in this context has not been
studied so far. hASCs are locally adjacent to epithelial breast
cancer cells and might represent early response cells within the
tumor stroma. Hence, the aim of this study was to investigate
whether carcinoma-associated myofibroblasts may originate from
hASCs. The present study revealed that a significant percentage of
hASCs differentiate into myofibroblast-like cells expressing alpha
smooth muscle actin (α-SMA) and tenascin-C when exposed to
conditioned medium from the human epithelial breast cancer cell
lines MDMAB231 and MCF7. This process is induced by transforming
growth factor beta 1 (TGFβ1) secreted from breast cancer cells. It
was shown that conditioned medium from MDMAB231 and MCF7 contains
significant amounts of TGFβ1. It could further be demonstrated that
the differentiation of hASCs towards myofibroblasts is dependent on
TGFβ1 signaling via phosphorylation of Smad2 and Smad3 in hASCs.
The induction of myofibroblasts can be abolished using a
neutralizing antibody to TGFβ1 as well as by pretreatment of hASCs
with SB431542, a selective inhibitor of the TGFβ1 activin
receptor-like kinases 4, 5 and 7. Additionally, hASC-derived
myofibroblasts exhibit functional properties of
carcinoma-associated myofibroblasts such as the increased secretion
of the tumor-promoting soluble factors SDF-1α and CCL5. Furthermore
hASC-derived myofibroblasts as well as conditioned medium from
these cells promote the in vitro invasion of MDAMB231 breast cancer
cells. Moreover inhibition of the TGFβ1 signaling pathway in hASCs
reduces the potential of these cells to enhance the invasion of
breast cancer cells. Overall, the data of the present study suggest
that human adipose tissue derived stem cells can differentiate into
carcinoma-associated myofibroblast under the influence of TGFβ1
secreted from breast cancer cells in vitro. The differentiation of
hASCs towards these tumor-promoting cells can be abolished by
targeting the TGFβ1 signaling pathway. Hence, inhibition of the
TGFβ1 signaling pathway may prove to be an interesting target for
breast cancer therapies. In vivo studies on the cancer
microenvironment under special consideration of the interactions
between hASCs and cancer cells should be of interest for breast
cancer research in the future.