Intra-tumor heterogeneity from a cancer stem cell perspective

Abstract

Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). The latter includes phenotypic diversity such as cell surface markers, (epi)genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure. Cancer stem cells (CSCs) have been put forward to be one of the determining factors that contribute to intra-tumor heterogeneity. However, recent findings have shown that the stem-like state in a given tumor cell is a plastic quality. A corollary to this view is that stemness traits can be acquired via (epi)genetic modification and/or interaction with the tumor microenvironment (TME). Here we discuss factors contributing to this CSC heterogeneity and the potential implications for cancer therapy.

Lung cancer stem cells—origin, characteristics and therapy

“…The cancer microenvironment is constituted of a thicker ECM than that found in the normal one. Tumor microenvironments holding different factors can also indirectly facilitate the tumor heterogeneity and resistance to chemotherapy (28,29).…”

Association of epithelial-to-mesenchymal transition circulating tumor cells in non-small cell lung cancer (NSCLC) molecular subgroups

“…Using the CellSearch assay, CTCs were initially isolated through their binding to ferrofluid particles coated with antibodies against the epithelial cell adhesion molecules (anti-EpCAM) and, subsequently, are stained with phycoerythrinconjugated anti-cytokeratin (recognizing predominantly cytokeratins 8, 18, and 19) and allophycocyanin-conjugated anti-CD45 (recognizing hematopoietic cells) antibodies, followed by 4',6-diamidino-2-phenylindole (DAPI) staining to fluorescently label the cell nuclei. The recent knowledge concerning the significant genetic and molecular heterogeneity that has been demonstrated both between patients (inter-tumor) and within a single tumor (intratumor) as well as the tumor evolution (7,8), requires the possibility of re-biopsies of the primary tumor as well as of the metastatic sites in order to have a real-time image of the molecular landscape of the disease; however, such re-biopsies are often difficult or even impossible in most patients. Therefore, the molecular and genetic analysis of CTCs along with study of the plasma cell tumor DNA (ctDNA), which are originated from both the primary tumor as well as the different metastatic sites, have been emerged as important tools to obtain real-time information for the molecular characteristics of the tumor.…”

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

“…Tumors and their microenvironment are incredibly heterogeneous structures, which behave like metabolic ecosystems [1–12]. In accordance with this cellular and metabolic heterogeneity, it is now well accepted that more than a single type of cancer cell exists [1–12].…”

“…In accordance with this cellular and metabolic heterogeneity, it is now well accepted that more than a single type of cancer cell exists [1–12]. For example, within a given epithelial cancer cell line (such as MCF7), there are “bulk” cancer cells (~ 85–95%; the majority of the population), as well as various types of progenitor cells (< 5%), and cancer stem cells (CSCs; < 1%).…”

“…Under these conditions, each 3D spheroid is clonally formed from a single CSC. For breast CSCs, these 3D spheroids are also known as tumor-spheres or mammo-spheres [1–12]. The generation of these 3D spheroids is thought to mimic the process of tumor formation and/or metastasis, providing an excellent model for drug discovery and functional validation.…”