Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy

Abstract

BackgroundBreast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).MethodsWe isolated a breast cancer cell population (CD44+CD24- cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44+CD24- phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.ResultsKnockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.ConclusionsKnockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.

Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem-like properties

“…During long doubling periods, CSCs avoid the anticancer effects of DNA damaging agents, mitotic spindle poisons and antimetabolites (Beier et al 2008;Ropolo et al 2009;Thomas and Cannas 2010), whereas differentiated cells with a rapid doubling time are easily affected by these agents. Recent further studies indicate that drug resistance is related to CD44 and PI3 kinase/Akt-related survival pathways as shown in breast tumor cells (Pham et al 2011;Cheng et al 2012;Van Phuc et al 2011;Tamada et al 2012). Thus, inhibition of CD44 can sensitize some types of cancer cells to antitumor drugs (Pham et al 2011;Tamada et al 2012) or inhibit tumor growth (Li et al 2008; Van Phuc et al 2011).…”

“…Recent further studies indicate that drug resistance is related to CD44 and PI3 kinase/Akt-related survival pathways as shown in breast tumor cells (Pham et al 2011;Cheng et al 2012;Van Phuc et al 2011;Tamada et al 2012). Thus, inhibition of CD44 can sensitize some types of cancer cells to antitumor drugs (Pham et al 2011;Tamada et al 2012) or inhibit tumor growth (Li et al 2008; Van Phuc et al 2011). The combination of DNA damaging drugs and inhibitors of the Akt pathway also inhibits CSC proliferation (Sabisz and Skladanowski 2009;Fan et al 2010;Zhang et al 2012).…”

Inflammatory Breast Cancer Stem Cells: Contributors to Aggressiveness, Metastatic Spread and Dormancy

“…Targeting HER2, a receptor thought to aid in the stem cell phenotype, may decrease this particular population of cells [69,70]. Small hairpin (sh) RNA targeting CD44 induces breast cancer stem cells to differentiate, resulting in a lower tumorigenic potential [70]. This putatively could reintroduce chemo-susceptibility in these breast cancer cells.…”

“…ALDH1 can metabolize chemotherapeutic drugs, and CD44+/CD24-cells are enriched in remaining breast tumor tissue following chemotherapy [71]. Targeting HER2, a receptor thought to aid in the stem cell phenotype, may decrease this particular population of cells [69,70]. Small hairpin (sh) RNA targeting CD44 induces breast cancer stem cells to differentiate, resulting in a lower tumorigenic potential [70].…”

“…It is suggested that breast cancer cells with stem cell-like properties are responsible for metastatic spread [68,69], while RhoC GTPase is expressed by highly metastatic cancer cells that exhibit "stemness" properties [30,70]. Cancer stem cells have also been linked to dormancy.…”