Challenges in the development of future treatments for breast cancer stem cells

Abstract

The recurrence of tumors after years of disease-free survival has spurred interest in the concept that cancers may have a stem cell basis. Current speculation holds that as few as 0.1% of the tumor mass may be chemoresistant and radioresistant, harboring stem-like properties that drive tumor survival, development, and metastasis. There are intense investigations to characterize cancer stem cells on the basis of self-renewal and multi-lineage differentiation. Thus far, no successful targeted therapies have been developed and reached the clinic, but as these cells are isolated and characterized, insights may be unraveled. In this review, we discuss the controversy over the origins of the cancer stem cell hypothesis and the unforeseen factors that may facilitate breast cancer stem cell survival and metastasis. We discuss the role of tumor microenvironment, including carcinoma-associated fibroblasts, epigenetic factors, and the Th1/Th2 balance, in supporting breast cancer stem cells. In addition, we have incorporated ideas on the epithelial-to-mesenchymal transition in metastatic dissemination of epithelial malignancies. This area is relevant since breast cancer stem cells have been suggested to revert to a mesenchymal phenotype during the progression of cancer. Finally we discuss prospects on developing targeted therapy including novel treatment modalities such as oncolytic viral therapy, differentiation therapy, and nanotechnology.

Growth inhibitory efficacy of natural products in a model for triple negative molecular subtype of clinical breast cancer

“…It occurs predominantly due to the emergence of drug-resistant stem cells (6,40,41). Data presented on the isolation and characterization of DOX-resistant triple negative MDA-MB-231 cells validate a potential model for stem cell-targeted therapy.…”

“…Select nuclear transcription factors Oct-3/4, Klf4, Sox2 and c-Myc (Yamanaka factors) are expressed in cancer stem cells derived from multiple organ sites (38)(39)(40)(41)(42)(43). These transcription factors are also essential for the induction of pluripotent stem cells derived from adult somatic cells (44)(45)(46)(47).…”

Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

“…Phenotypic resistance to chemoendocrine therapy has been effectively used for the isolation of putative drug-resistant CISC (2,4,(10)(11)(12). In the present study, the experiments designed to isolate drug-resistant phenotypes from the models for luminal A, HER-2-enriched and triple negative breast cancer utilized TAM, 4-HPR and DOX, respectively, for the selective expansion of the resistant phenotypes, since these agents have been used for the clinical management of the aforementioned molecular subtypes of breast cancer (6)(7)(8).…”

“…CISC are characterized by a unique self-renewal program, enhanced tumorigenic potential and resistance to conventional therapeutic interventions (1)(2)(3)(4). Thus, reliable cell culture models for clinical CISC may constitute useful experimental approaches for the development of novel cancer stem cell-targeted therapies for the treatment of chemoendocrine therapy-resistant clinical breast cancer.…”

“…However, the long-term use of small molecule inhibitor-based targeted chemoendocrine therapy is frequently associated with de novo or acquired tumor resistance, which compromises the therapeutic efficacy of the treatment and promotes the progression of therapy-resistant disease in patients affected by these molecular subtypes of breast cancer (6)(7)(8)(9). Therapy-resistant CISC are considered to be responsible for the progression of metastatic disease (2,4). Therefore, experimental approaches that enable the isolation and characterization of putative CISC are essential for the identification of promising stem cell-targeted therapeutic lead compounds.…”