CD44+/CD24−/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome

Idowu, Michael O.; Kmieciak, Maciej; Dumur, Catherine I.; Burton, Regina S.; Grimes, Margaret M.; Powers, Celeste N.; Manjili, Masoud H.

doi:10.1016/j.humpath.2011.05.005

Cited by 230 publications

(204 citation statements)

References 38 publications

(55 reference statements)

Supporting

Mentioning

183

Contrasting

Unclassified

Order By: Relevance

“…Additionally, the expression of stem cell factors increased after CAF treatment in vitro, which relates to poor prognosis and increased risk of metastases. 24,25 Therefore, application of chemotherapy leads to a more mesenchymal tumor phenotype in this model. A mesenchymal phenotype of epithelial tumors corresponds to higher aggressiveness and poor prognosis.…”

Section: Discussionmentioning

confidence: 92%

Chemotherapy of WAP‐T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

Jannasch¹,

Wegwitz

Lenfert

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

In this study, the effects of the standard chemotherapy, cyclophosphamide/adriamycin/5-fluorouracil (CAF) on tumor growth, dissemination and recurrence after orthotopic implantation of murine G-2 cells were analyzed in the syngeneic immunocompetent whey acidic protein-T mouse model (Wegwitz et al., PLoS One 2010; 5:e12103; Schulze-Garg et al., Oncogene 2000; 19:1028-37). Single-dose CAF treatment reduced tumor size significantly, but was not able to eradicate all tumor cells, as recurrent tumor growth was observed 4 weeks after CAF treatment. Nine days after CAF treatment, residual tumors showed features of regressive alterations and were composed of mesenchymal-like tumor cells, infiltrating immune cells and some tumor-associated fibroblasts with an intense deposition of collagen. Recurrent tumors were characterized by coagulative necrosis and less tumor cell differentiation compared with untreated tumors, suggesting a more aggressive tumor phenotype. In support, tumor cell dissemination was strongly enhanced in mice that had developed recurrent tumors in comparison with untreated controls, although only few disseminated tumor cells could be detected in various organs 9 days after CAF application. In vitro experiments revealed that CAF treatment of G-2 cells eliminates the vast majority of epithelial tumor cells, whereas tumor cells with a mesenchymal phenotype survive. These results together with the in vivo findings suggest that tumor cells that underwent epithelial-mesenchymal transition and/or exhibit stem-cell-like properties are difficult to eliminate using one round of CAF chemotherapy. The model system described here provides a valuable tool for the characterization of the effects of chemotherapeutic regimens on recurrent tumor growth and on tumor cell dissemination, thereby enabling the development and preclinical evaluation of novel therapeutic strategies to target mammary carcinomas.Mammary carcinoma is the most frequent type of cancer in women in the Western world.1 About 25% of the patients develop distant metastases and ultimately die of breast cancer. 2 The prognosis of cancer patients is largely determined by the occurrence of distant metastases. Disseminated tumor cells (DTCs) in the bone marrow at diagnosis and during follow-up have been demonstrated in several early breast cancer studies to be of clinical relevance 3,4 and are used in patient risk assessment.The high incidence of breast cancer and the high mortality of the disease ask for better treatment options. However, a major problem in evaluating the effects of cancer therapy in preclinical settings results from the fact that the main parameter analyzed is tumor growth, and treatment effects on DTCs are not monitored. Especially, for treating mammary carcinomas, strategies to target DTCs and metastases are absolutely essential, as they are known to disseminate at an early stage. 5Most preclinical studies are performed using xenograft models implanting human tumor cells into immunocompromised mice, which only inadequately mimic tumor de...

show abstract

Section: Discussionmentioning

confidence: 92%

Chemotherapy of WAP‐T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

Jannasch¹,

Wegwitz

Lenfert

et al. 2014

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Elevated CD44 expression in the peritumor stroma is associated with increased relapse (37), and in primary BCa cell subsets may contribute to tumor initiation and progression (38)(39)(40). Elevated RHAMM expression in BCa tumor subsets is a prognostic indicator of poor outcome and increased metastasis (22,33,41).…”

Section: Significancementioning

confidence: 99%

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Veiseh

Kwon

Borowsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA −/low vs. HA high ) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA −/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.tumor cell heterogeneity | hyaluronan binding | heterogeneity index B reast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1-3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3-12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13-15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16-18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan-BCa cell receptor interactions. We reasoned this approach...

show abstract

“…5 Triple-negative breast cancers (TNBCs) are enriched for stem-like breast cancer cells (CD44 C / CD24 ¡/low ), which are typically aggressive and highly resistant to current therapies. [6][7][8][9] These stem-like breast cancer cells produce high levels of IL-6, and have the capacity to metastasize. 10 Moreover, IL-6 is capable of converting dormant breast cancer cells into an actively growing tumor.…”

Section: Introductionmentioning

confidence: 99%

Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer

et al. 2015

View full text Add to dashboard Cite

Keywords: adjuvant, cryoablation, immunogenic tumor cell death, Mage-b, Meriva, metastatic breast cancer, Survivin, triple-negative breast cancer, vaccinesInterleukin-6, a cytokine produced particularly by triple-negative breast cancers, strongly inhibits T cell responses in the tumor microenvironment. Here we tested cryoablation combined with Meriva (a lecithin delivery system of curcumin with improved bioavailability) in mice with metastatic breast cancer (4T1). Cryoablation involves killing of tumor cells through freezing and thawing, resulting in recruitment of tumor-specific T cells, while curcumin stimulates T cells through the reduction of IL-6 in the TME. Cryoablation plus Meriva accumulated and activated CD8C T cells to multiple tumor-associated antigens such as Mage-b and Survivin (both expressed by 4T1 tumors). This correlated with a nearly complete reduction of 4T1 primary tumors and lung metastases while little effect was observed from saline or Meriva alone (28 d after tumor cell injection). The survival rate in the group of cryoablation plus Meriva was significantly improved compared to all control groups. Using a less aggressive 4T1 model expressing luciferase (4T1.2luc3), we demonstrated that all mice receiving saline or Meriva developed metastases in the lungs and a primary tumor (38 d after tumor cell injection; and died soon after that), but not the mice receiving cryoablation or cryoablation plus Meriva. However, on day 58 the mice receiving cryoablation developed 4T1.2luc3 metastases in the lungs, while mice receiving cryoablation plus Meriva were free of metastases. These results strongly suggest that cryoablation delayed the development of lung metastases on the short-term, but Meriva administered after cryoablation was significantly better in delaying the development of lung metastases and survival on the long-term.

show abstract

CD44+/CD24−/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome

Cited by 230 publications

References 38 publications

Chemotherapy of WAP‐T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

Chemotherapy of WAP‐T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer

Contact Info

Product

Resources

About