Chemo-resistance in Triple Negative Breast Cancer Linked To Mesenchymal Stem Cells In Tumor

Mesenchymal 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 journal in July 2017. Importance of Knowing the Cause of Chemoresistance in TNBC

Triple negative breast cancer remains one of the most aggressive types of breast cancer. 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.

Many theories have been put forward to explain this drug resistance, 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

• 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).
• Doxorubicin 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.

Findings of The Study

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 (DMEM).
• 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 in MDA-MB-231 triple negative breast cancer cells by upregulation of ABCG2 protein.

ABCG2 and Its Role in Breast Cancer

Advertisement

ATP-binding 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 (foreign chemical not innate to the body), and may play a role in multi-drug resistance to chemotherapeutic agents including mitoxantrone and camptothecin analogues.

Advertisement

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 ABCG2 gene and development of doxorubicin resistance.

Mesenchymal 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 explored.

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 cancer.

References:

1. Wei-Lan Yeh, Cheng-Fang Tsai and Dar-Ren Chen,Stem Cell Research & Therapy, https://doi.org/10.1186/s13287-017-0630-2

Source-Medindia