Dataset Information

Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

ABSTRACT: The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tumors of several transgenic mouse models to determine their tumor-initiating cell frequency. We determined whether the tumors that formed following tumor cell transplantation phenocopied the primary tumors from which they were isolated and whether they could be serially transplanted. Finally we investigated whether propagating primary tumor cells in different tissue culture conditions affected their resident tumor-initiating cell frequency. We found that tumor-initiating cells comprised between 15% and 50% of the bulk tumor cell population in multiple independent mammary tumors from three different transgenic mouse models of breast cancer. Culture of primary mammary tumor cells in chemically-defined, serum-free medium as non-adherent tumorspheres preserved TIC frequency to levels similar to that of the primary tumors from which they were established. By contrast, propagating the primary tumor cells in serum-containing medium as adherent populations resulted in a several thousand-fold reduction in their tumor-initiating cell fraction. Our findings suggest that experimental conditions, including the sensitivity of the transplantation assay, can dramatically affect estimates of tumor initiating cell frequency. Moreover, conditional on cell culture conditions, the tumor-initiating cell fraction of bulk mouse mammary tumor cell preparations can either be maintained at high or low frequency in vitro thus permitting comparative studies of tumorigenic and non-tumorigenic cancer cells.

SUBMITTER: Kurpios NA

PROVIDER: S-EPMC3608640 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

Kurpios Natasza A NA Girgis-Gabardo Adele A Hallett Robin M RM Rogers Stephen S Gludish David W DW Kockeritz Lisa L Woodgett James J Cardiff Robert R Hassell John A JA

PloS one 20130326 3

The tumor-initiating cell (TIC) frequency of bulk tumor cell populations is one of the criteria used to distinguish malignancies that follow the cancer stem cell model from those that do not. However, tumor-initiating cell frequencies may be influenced by experimental conditions and the extent to which tumors have progressed, parameters that are not always addressed in studies of these cells. We employed limiting dilution cell transplantation of minimally manipulated tumor cells from mammary tum ...[more]

PMID: 23555570

Similar Datasets

Project description:Liver metastasis, characterized by the spread of tumors to the liver from other areas, represents a deadly disease with poor prognosis. Currently, there is no effective therapeutic strategies and/or agents to combat liver metastasis primarily due to the insufficient understanding of liver metastasis. To develop a promising strategy for targeting liver metastasis, understanding of a cell origin responsible for liver metastasis and how this cell can be pharmacologically eliminated are therefore crucial. Using diverse tumor models including p53 -/- genetic mouse model and syngeneic tumor models, we identified primordial germ cell (PGC)-like tumor cells, which are enriched in earliest liver micro-metastasis (up to 99%), as a cell origin of liver metastasis. PGC-like tumor cells formed earliest micro-metastasis in liver and gradually differentiated into non-PGC-like tumor cells to constitute late macro-metastasis in the course of tumor metastasis. The liver metastasis-initiating cells (PGC-like tumor cells) display cell renewal and differentiation capabilities, resemble primordial germ cells (PGCs) in morphology and PGC marker gene expression, and express higher level of the genes linked to metastasis and immune escape compared with non-PGC-like tumor cells. Of note, Stellarhigh PGC-like tumor cells, but not Stellarlow non-PGC-like cells, sorted from primary tumors of p53 -/- mice readily form liver metastasis. Depletion of PGC-like tumor cells through genetic depletion of any of key germ cell genes impairs liver metastasis, while increased PGC-like tumor cells by SMAD2 knockout is correlated with markedly enhanced liver metastasis. Finally, we present the proof of principle evidence that pharmacologically targeting BMP pathways serves as a promising strategy to eliminate PGC-like tumor cells leading to abrogating liver metastasis. Collectively, our study identifies PGC-like tumor cells as a cell origin of liver metastasis, whose depletion by genetically targeting core PGC developmental genes or pharmacologically inhibiting BMP pathways serves a promising strategy for targeting liver metastasis.

Project description:The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to sub-populations of less-differentiated cells residing within the tumor. These sub-populations of tumor cells, termed tumor-initiating cells, may be isolated from heterogeneous tumors when sorted or cultured in defined medium designed for enrichment of the tumor-initiating cells. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. These meningioma-initiating cells (MICs) self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted into athymic nude mice. Immunohistochemistry reveals protein expression patterns similar to neural stem and progenitor cells while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Furthermore, microarray analysis of gene expression reveals that many epithelial to mesenchymal transition genes are upregulated in the MICs, consistent with the presence of both neural stem cell and mature neural cell molecular markers seen in the derived cultures. Pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16INK4A), p14ARF, and CDKN2B (p15INK4B). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. In conclusion, we identify a tumor-initiating population from an atypical meningioma that displays a unique phenotype and these results provide increased understanding of atypical meningioma progression. Part 1 of 2: Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from primary tissue and their counterpart cell lines Part 2 of 2: Illumina gene expression array analysis was performed according to the manufacturer's directions on RNA extracted from cultured primary Meningioma and neural stem cell lines

Dataset Information

Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

Publications

Single unpurified breast tumor-initiating cells from multiple mouse models efficiently elicit tumors in immune-competent hosts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets