ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas

Adams, A.E.; Warner, Kristy A.; Pearson, Alexander T.; Zhang, Zhaocheng; Kim, Hong Sun; Mochizuki, Daiki; Basura, Gregory J.; Helman, Joseph I.; Mantesso, Andréa; Castilho, Rogerio M.; Wicha, Max S.; Nör, Jacques E.

doi:10.18632/oncotarget.5782

Cited by 64 publications

(80 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tumor cell lines derived from primary and metastatic MEC were established in the Nör laboratory at the University of Michigan [26, 30]. We examined histone H3 acetylation in 5 MEC cell lines, including UM-HMC1, UM-HMC2, UM-HMC3A, UM-HMC3B, and UM-HMC5.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

Mucoepidermoid carcinoma (MEC) is the most common malignancy of salivary glands. The response of MEC to chemotherapy is unpredictable, and recent advances in cancer biology suggest the involvement of cancer stem cells (CSCs) in tumor progression and chemoresistance and radioresistance phenotype. We found that histone acetyltransferase inhibitors (HDACi) were capable of disrupting CSCs in MEC. Furthermore, administration of HDACi prior to Cisplatin (two-hit approach) disrupts CSCs and sensitizes tumor cells to Cisplatin. Our findings corroborate to emerging evidence that CSCs play a key role in tumor resistance to chemotherapy, and highlights a pharmacological two-hit approach that disrupts tumor resistance to conventional therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Recent advances in MEC biology have occurred through the identification of a subpopulation of CSCs with high tumorigenic properties [26]. However, the role of CSCs in chemoresistance in MEC is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is known that ALDH activity and CD44 expression can be used to identify cancer stem cells (CSC) in salivary gland tumors (23–26). To elucidate the impact of MI-773 and/or Cisplatin treatment on ACC cancer stem cells, mice harboring UM-HACC-PDX-5 tumors were divided in 4 groups (n=5) and received MI-773 (200 mg/kg) for one week, combined or not with two single doses of Cisplatin (at the 1 st and 7 th day) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Salivary gland cancer stem cells were identified as ALDH high CD44 high cells, as previously described (25,26). UM-PDX-HACC-5 tumors were collected, cut in small pieces, and dissociated using the GentleMACS dissociator kit (Miltenyi Biotec), incubated in ACK red blood cell lysis buffer (Invitrogen), and filtered through a 40-µm sterile cell strainer.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Nör

Warner

Zhang

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the anti-tumor effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) combined with Cisplatin in patient-derived xenograft (PDX) ACC tumors. Experimental design Therapeutic strategies with MI-773 and/or Cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells was determined by flow cytometry for ALDH activity and CD44 expression. Results Combined therapy with MI-773 with Cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL and active Caspase-9 upon MI-773 treatment. Both, single-agent MI-773, and MI-773 combined with Cisplatin, decreased the fraction of cancer stem cells in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a post-surgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (p=0.0097). Conclusions Collectively, these data demonstrate that therapeutic inhibition of MDM2-p53 interaction by MI-773 decreased the cancer stem cell fraction, sensitized ACC xenograft tumors to Cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2-p53 interaction.

show abstract

“…Recently, Adams and co-workers have shown that MEC have a small fraction of cells with high tumourigenic potential (17). ALDH high /CD44 high cells isolated from MEC showed higher ability to form primary and secondary salispheres in vitro when compared to ALDH low / CD44 low cells as well as generate MEC in vivo characterized by abundant intermediate-like cells, with spindle shape, oval nuclei and highly anaplastic areas.…”

Section: Introductionmentioning

confidence: 99%

Embryonic stem cells markers Oct4 and Nanog correlate with perineural invasion in human salivary gland mucoepidermoid carcinoma

Rodrigues

Sedassari

Esteves

et al. 2016

J Oral Pathology Medicine

View full text Add to dashboard Cite

show abstract

ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas

Cited by 64 publications

References 51 publications

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas

Embryonic stem cells markers Oct4 and Nanog correlate with perineural invasion in human salivary gland mucoepidermoid carcinoma

Contact Info

Product

Resources

About