The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications

Abstract

Cancer stem cells (CSCs) are tumor cells that possess the capacity to divide asymmetrically, producing one stem cell (self-renewal) and one progenitor cell that is able to generate heterogeneous lineages of the cancer cells that comprise tumors. CSCs in human breast tumors were initially identified in 2003 by Al-Hajj et al, 1 who discovered a cellular population characterized by the cell-surface markers CD44 ϩ /CD24 Ϫ/low /ESA ϩ and lack of expression of CD2, CD3, CD10, CD16, CD18, CD31, CD64, and CD140b (lineage Ϫ ). As few as 200 of these cells were able to form tumors when xenotransplanted into NOD/SCID mice, whereas tens of thousands of other cells could not.1 The tumors generated recapitulated the phenotypic heterogeneity of the parental tumor, containing a minority of CD44 ϩ /CD24 Ϫ/low /lineage Ϫ cells that can be serially passaged to form new tumors.1 The CD44 ϩ /CD24 Ϫ phenotype has been used extensively to identify and isolate breast cancer cells with increased tumorigenicity.Putative breast CSCs have also been isolated from patient samples after in vitro propagation and from breast cancer cell lines, through their ability to proliferate in suspension as nonadherent spheres (mammospheres). 1-4Because the capacity to form mammospheres is increased in early progenitor/stem cells, this system has been widely used as an indirect measurement of the number of cells with self-renewal capability. 5,6 In accord with in vivo data, mammospheres from breast cancer cells are enriched in cells with the CD44 ϩ /CD24 /CD24Ϫ retain self-renewal capability, other markers for human breast CSCs have been investigated. Activity of the aldehyde dehydrogenase (ALDH) family of cytosolic isoenzymes is inSupported in part by PASPA-UNAM (Programa de Apoyos para la Superación del Personal Académico-Universidad Nacional Autónoma de México) (M.A.V.-V.) and the NIH (grants R01CA070896, R01CA075503, R01CA107382, R01CA132115, and R01CA086072 to R.G.P. and R01CA120876 to M.P.L.). The Kimmel Cancer Center was supported by an NIH cancer center core grant (P30CA56036 to R.G.P.). This project is funded in part from the Marian C. Falk Medical Research Trust and a grant from the Pennsylvania Department of Health (R.G.P.).

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

“…1,4,24 Based on this, BCSCs are regarded as novel therapeutic targets. 38,39 BCSCs are enriched in the ALDH C cell population, which has the potential to generate mammospheres under anchorage-independent conditions in mammosphere culture medium.…”

“…Based on these observations, the BCSCs have become the foundation for new preventive and therapeutic strategies in breast cancer. 1,[4][5][6] CSCs have been identified and isolated using putative cell surface markers. [7][8][9] It is reported that BCSCs have been enriched in CD44…”

An agent-based model of cancer stem cell initiated avascular tumour growth and metastasis: the effect of seeding frequency and location

“…Specifically, there is increasing evidence that this is the case in breast [5,6], colorectal [7][8][9] and skin cancer [9][10][11], to name a few. There is increasing support for the importance of cancer stem cells (CSC) in the process of metastatic dissemination and colonization [12][13][14]. It is generally accepted that different primary cancers have organ-specific sites for metastasis [15].…”

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

“…Together these findings suggest that GTCpFE may also be a promising, clinically relevant anti-inflammatory molecule for eradicating breast CSCs by exploiting CSC's reliance on multiple inflammatory pathways, including the NFĸB pathway and the cyclooxygenase 2-prostaglandin E2 axis [16][17][18][19][20][21]30 . Targeting breast CSCs is important because they are thought to contribute to therapy resistance, recurrence and metastasis [31][32][33][34] .…”