Leading edge or tumor core: Intratumor cancer stem cell niches in oral cavity squamous cell carcinoma and their association with stem cell function

Chowdhury, Farshad N.; Reisinger, Julie; Gomez, Karina E.; Chimed, Tugs-Saikhan; Thomas, Carissa M.; Le, Phuong N.; Miller, Bettina; Morton, J. Jason; Nieto, Cera; Somerset, Hilary; Wang, Xiaojing; Keysar, Stephen B.; Jimeno, Antonio

doi:10.1016/j.oraloncology.2019.09.011

Cited by 13 publications

(10 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The researchers found that in some tumor types, high stem cell index was associated with mutation. For example, in squamous cell carcinoma of the head and neck, high stem cell index was found to be related to NSD1 gene mutation 13 . In addition, it could recognize molecules associated with the dedifferentiation of certain tumors.…”

Section: Introductionmentioning

confidence: 99%

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Bai

Shu

et al. 2020

Cancer Medicine

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are characterized by self‐renewal and ‐differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell‐related genes in LIHC. We found that mRNA expression‐based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co‐expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA‐binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Bai

Shu

et al. 2020

Cancer Medicine

View full text Add to dashboard Cite

show abstract

“…We previously demonstrated the invasive potential of CUHN013 PDXs lies at the tumor edge (28). As seen in the coculture Inv model, VCAM-1 had higher expression at the edge in both NSG and HM tumors (Supplementary Fig.…”

Section: Ha Serves As the Link Between Growth-and Invasion-promoting Pathwaysmentioning

confidence: 61%

“…S1, top). Previously, we have shown regional variations in CSC distribution within HNSCCs, and how CSCs from different regions have distinct characteristics in terms of proliferative versus invasive potential, suggesting the importance of stromal influence on CSC function (28). Because TAMs are critical in HNSCC growth (26), we assessed their prevalence in HPV-positive and HPV-negative HNSCC patient samples, and found TAM infiltration (measured by CD163 and CD68 staining) varied between regions of the same tumor (Supplementary Fig.…”

Section: Tam Distribution In the Tme In Hnscc And Link To Csc Expressionmentioning

confidence: 94%

Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying crosstalk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCCderived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respec-tively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals.Significance: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.

show abstract

“…It is found that the signal in the tumor edge increases immediately after the injection and keeps a much higher SNR than the interior. Considering the heterogeneity of the tumor, especially a greater fraction of cancer stem cells in the proliferative phase in the edge, − we ascribe this phenomenon to the features related to tumor growth, such as enhanced vascular permeability. As a hallmark of malignancy, rapid angiogenesis is always synchronized with cancer cell proliferation, leading to leaky vessels, thereby allowing nanoparticles access to the interstitial space of the tumor edge. , …”

Section: Resultsmentioning

confidence: 99%

A pH-Activatable MnCO₃ Nanoparticle for Improved Magnetic Resonance Imaging of Tumor Malignancy and Metastasis

Zhu

Xiong

Zhou

et al. 2021

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

Engineered magnetic nanoparticles have been extensively explored for magnetic resonance imaging (MRI) diagnosis of a tumor to improve the visibility. However, most of these nanoparticles display “always-on” signals without tumor specificity, causing insufficient contrast and false positives. Here, we provide a new paradigm of MRI diagnosis using MnCO3 nanorhombohedras (MnNRs) as an ultrasensitive T 1-weighted MRI contrast agent, which smartly enhances the MR signal in response to the tumor microenvironment. MnNRs would quickly decompose and release Mn2+ at mild acidity, one of the pathophysiological parameters associated with cancer malignancy, and then Mn2+ binds to surrounding proteins to achieve a remarkable amplification of T 1 relaxivity. In vivo MRI experiments demonstrate that MnNRs can selectively brighten subcutaneous tumors from the edge to the interior may be because of the upregulated vascular permeation at the tumor edge, where cancer cell proliferation and angiogenesis are more active. Specially, benefiting from the T 2 shortening effect in normal liver tissues, MnNRs can detect millimeter-sized liver metastases with an ultrahigh contrast of 294%. The results also indicate an effective hepatic excretion of MnNRs through the gallbladder. As such, this pH-activatable MRI strategy with facility, biocompatibility, and excellent efficiency may open new avenues for tumor malignancy and metastasis diagnosis and holds great promise for precision medicine.

show abstract

Leading edge or tumor core: Intratumor cancer stem cell niches in oral cavity squamous cell carcinoma and their association with stem cell function

Cited by 13 publications

References 37 publications

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells

A pH-Activatable MnCO₃ Nanoparticle for Improved Magnetic Resonance Imaging of Tumor Malignancy and Metastasis

Contact Info

Product

Resources

About

Leading edge or tumor core: Intratumor cancer stem cell niches in oral cavity squamous cell carcinoma and their association with stem cell function

Cited by 13 publications

References 37 publications

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Identification of cancer stem cell characteristics in liver hepatocellular carcinoma by WGCNA analysis of transcriptome stemness index

Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells

A pH-Activatable MnCO3 Nanoparticle for Improved Magnetic Resonance Imaging of Tumor Malignancy and Metastasis

Contact Info

Product

Resources

About

A pH-Activatable MnCO₃ Nanoparticle for Improved Magnetic Resonance Imaging of Tumor Malignancy and Metastasis