- Mesenchymal stem cells or stromal cells are an integral part of any
cancer milieu including breast cancer and play a key part in tumor
initiation, progression and spread.
- Current study suggests that human adipose tissue derived
mesenchymal stem cells in the tumor could cause chemo-resistance in triple negative
stem cells within the tumor might contribute to chemo-resistance in triple negative breast cancer according
to a recent study conducted at the Changhua Christian
Hospital in Taiwan. The findings of this study appeared in the Stem Cell Research and Therapy
in July 2017.
of Knowing the Cause of Chemoresistance in TNBC
Triple negative breast cancer
remains one of the most aggressive types of breast
. Chemotherapy is the mainstay of treatment and despite a seemingly
favorable response initially, the relapse
within 3-5 years of treatment remains rather high
. The recurrent tumors
become resistant to the original chemotherapy resulting in spread of the tumor
to other sites and death.
‘Future research should focus on the development of novel treatment modalities to overcome chemo-resistance in triple negative breast cancer attributed to human adipose tissue derived stem cells (hADSCs).’
Many theories have been put forward to
explain this drug
although experts believe that the tumor microenvironment
could play a role in this phenomenon.
The current study aims to investigate the possible role of the fat
tissue derived mesenchymal stem cells in causing chemo-resistance
in triple negative breast cancer. A knowledge of the possible mechanism of
mesenchymal stem cells in causing chemo-resistance in TNBC
could pave the way for research to
develop newer therapeutic targets and options that would help overcome drug
resistance in TNBC with improved patient prognosis
. Conduct of The Study and Important Findings
of The Study
- The study was undertaken at the
Changhua Christian Hospital in Taiwan. With prior written and informed
consent, the fat tissue surrounding the tumor was obtained from the
mastectomy samples of women who had surgery for breast cancer.
- Mesenchymal stem cells were isolated
from these adipose tissue samples after a 24 hour period.
- The obtained hADSCs were cultured in
modified Dulbecco's modified Eagle's medium (DMEM). Following the growth of hADSCs for a certain period of time,
the DMEM would contain the
factors or chemicals secreted by these cells and is referred to as hADSCs conditioned medium (CM).
- Furthermore, MDA-MB-231 cells which are breast cancer derived cell lines
available commercially, were employed
to test for doxorubicin resistance in the original medium (i.e. in
which these cell lines were initially incubated) and also following
incubation in the conditioned medium (CM).
was employed in the study to test for development of resistance, since in
most cases, doxorubicin is the first
line of therapy for breast cancer.
The notable observations of the research
team included the following:
- Several secretory factors and
cytokines were released into the conditioned medium by the cultured
hADSCs, the most abundant being CXCL1, CCL5 and IL-8.
- Among the above cytokines, human
recombinant CXCL1 was found to dose-dependently enhance ABCG2 protein
expression in hADSCs conditioned medium. The upregulation of ABCG2 was in
turn mediated by the downregulation of miR-106a (microRNA-106a).
- Significant MDA-MB-231 cell death
was observed from 8 hours doxorubicin treatment in both the original
medium (L15) used for maintaining MDA-MB-231 cells and fresh medium
- However, CM (DMEM in which peri-foci
hADSCs were cultured) in which peri-tumor hADSCs were cultured
demonstrated significantly reduced doxorubicin-induced cell death,
suggesting development of doxorubicin resistance.
The findings of the study appear to
suggest that hADSCs derived CXCL1 factor
mediates doxorubicin resistance
triple negative breast cancer cells by
upregulation of ABCG2
and Its Role in Breast Cancer
cassette sub-family G member 2 is a protein coded for by the ABCG2
gene. The ABC proteins are involved in transport of various molecules across
extracellular and intracellular membranes.
Also referred to as the Breast
Cancer Resistance Protein, this
protein plays an important role in the transport of xenobiotics
chemical not innate to the body), and may play a role in multi-drug resistance
to chemotherapeutic agents including mitoxantrone and camptothecin analogues.
MicroRNAs (miRNAs) are a group of small
(20 to 25 nt) noncoding RNAs able to
regulate gene expression
. In this study, downregulation of miR-106a was associated with increased expression of
and development of doxorubicin resistance.
Stem Cells and Cancer
Mesenchymal stem cells are recruited into tumor foci and
reprogrammed by the cancer cells to enhance tumor growth, progression and metastasis
Although these effects of mesenchymal stem cells have been described in many
earlier studies, their role in promoting drug resistance has not been fully
In conclusion, this study has shown a
possible role and mechanism by which chemo-resistance develops
in TNBC. Further studies will be needed to gain more insight into the processes
involved and to focus on developing newer treatment options, possibly targeting
mesenchymal stem cells to overcome the drug resistance in triple negative breast
- Wei-Lan Yeh, Cheng-Fang Tsai and Dar-Ren Chen,Stem Cell Research & Therapy, https://doi.org/10.1186/s13287-017-0630-2