Correction: Colorectal Cancer Stem Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy

Abstract

Background: Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. The subpopulation of human colorectal tumor cells with an ESA + CD44 + phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. CoCSC). We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.Methods and Findings: Xenogeneic tumors initiated with CoCSC were allowed to reach ,400 mm 3 , at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Aldehyde dehydrogenase 1 gene expression and enzymatic activity are elevated in CoCSC and using an in vitro culture system that maintains CoCSC as demonstrated by serial transplants and lentiviral marking of single cell-derived clones, we further show that ALDH1 enzymatic activity is a major mediator of resistance to cyclophosphamide: a classical chemotherapeutic agent.Conclusions: CoCSC are enriched in colon tumors following chemotherapy and remain capable of rapidly regenerating tumors from which they originated. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy.

Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study

“…Therefore, by impairing cell proliferation, migration, anoikis evasion, anchorage-independent cell growth, self-renewal potential and stemness, natural ITC-enriched extracts obtained by high-pressure extraction with supercritical CO 2 may represent a promising therapeutic strategy for CRC in a context of coadjutant therapies or in alternative to conventional chemotherapeutic drugs, since they target crucial aspects of tumor progression and the CSC-like phenotype that are negligently targeted under the conventional methods that often result in tumor recurrence [7,8]. …”

“…Tumor recurrence can be attributed to cancer stem cells (CSCs) that can prevail even after chemotherapy, hindering CRC eradication and favoring a high incidence of tumor relapse [7,8]. CD133 (Prominin-1) and LGR5 (Leucine-rich repeat-containing G-protein coupled receptor 5) have been considered as putative colorectal CSC markers related with proliferation, invasion, metastasis and chemoresistance [9,10,11].…”

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

“…A small population in the tumors, "cancer stem cells or CSCs", is also believed to have pivotal roles in cancer initiation, resistance and metastasis [4]. Ironically, many therapeutic approaches, including radiation and chemotherapeutic agents, may even induce CSC number and the potentials [5][6][7]. This CSC population may share many normal stem cell-like characteristics, and therefore, it is difficult to eliminate with the BCC-targeting strategies.…”

Revisiting the Role of Exosomes in Colorectal Cancer: Where Are We Now?

“…Apart from classical mechanisms associated with resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA), including the alteration of cellular drug influx/efflux, enhancement of drug inactivation and single nucleotide polymorphisms (SNPs) of fluoropyrimidine or platinum targets (50), the acquisition of cancer stemness has been proposed as a possible way to induce chemoresistance in CRC (51). Cancer stem cells (CSCs) are endowed with indefinite self-renewal activity and maintain the ability to generate both tumorigenic and non-tumorigenic cells.…”