Clinical significance of putative cancer stem cell marker CD44 in different histological subtypes of lung cancer

Roudi, Raheleh; Madjd, Zahra; Korourian, Alireza; Mehrazma, Mitra; Molanae, Saadat; Sabet, Mehrdad Nasrollahzadeh; Shariftabrizi, Ahmad

doi:10.3233/cbm-140424

Cited by 43 publications

(21 citation statements)

References 44 publications

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“…The latters display several stem cell-associated properties including self-renewal capability, higher clonogenic potential, resistance to chemotherapy and the expression of diverse CSCs markers, such as CD133, ALDH1 (detected as ALDH activity), Nanog and CD44. Noteworthy, none of analyzed markers showed a high and consistent expression in all the spheroids patient-derived LCSC lines, that were used in this study, thus confirming the heterogeneity in lung CSCs marker expression [46][47][48]. Our results show that CPTH6 preferentially inhibits cell viability and activates the apoptotic program of spheroid LCSCs with properties of CSCs.…”

Section: Discussionsupporting

confidence: 60%

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

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Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl] hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.

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Section: Discussionsupporting

confidence: 60%

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Martile¹,

Desideri²,

Luca³

et al. 2016

European Journal of Cancer

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“…cd44 is commonly considered to be a cancer stem cell marker and it is found overexpressed in lung cancer tissues especially in lung cancer stem cells. High expression of CD44 in lung cancer tissue was significantly correlated with poor prognosis of NSCLC patients (24). A previous finding showed that the absence of CD44 in lung cancer cells could result in suppression of cancer stem cell properties including downregulation of tumor occurrence and reversing multi-drug resistance (25).…”

Section: Discussionmentioning

confidence: 87%

CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells

Yin

Zhang

et al. 2020

Int J Mol Med

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cluster of differentiation 44 (cd44) as a transmembrane glycoprotein is found to be expressed in non-small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild-type NSCLC cells to cisplatin and how it affects wild-type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild-type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G 0 /G 1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44-silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild-type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild-type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild-type NScLc.

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“…In a combined group of pulmonary and gastrointestinal neuroendocrine neoplasms originally described as carcinoids, the patients with lymph node or distant metastasis lacked CD44 in the tumours significantly more frequently [85]. Thus, the prognostic role of CD44 expression in NENs is different from the negative findings in many carcinomas, including pancreatic ductal adenocarcinoma, gastric adenocarcinoma, clear cell renal carcinoma or non-small cell lung carcinoma, among others [11,[86][87][88]. In our study, there also was no association between CD44 and such morphological parameters, such as high grade and stage, which are indicative of a poor prognosis.…”

Section: Cd44mentioning

confidence: 99%

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

Simtniece¹,

Vanags²,

Štrumfa³

et al. 2015

pjp

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The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann-Whitney and Kruskal-Wallis methods were applied; p < 0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p = 0.022), the World Health Organization 2004 and 2010 classification grades (p = 0.021 and p = 0.002), stage (p = 0.028) and mitotic count (p = 0.007) but among molecular markers -with CK19 (p = 0.033) and vimentin (p = 0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p = 0.018), pR (p = 0.025), vascular (p = 0.020), perineural (p = 0.026) and lymphatic invasion (p = 0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth.

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Clinical significance of putative cancer stem cell marker CD44 in different histological subtypes of lung cancer

Abstract: CD44 could be a valuable tool for the study of lung CSCs and provide a novel therapeutic target for treatment of the patients with lung cancer in combination with conventional therapy.

Cited by 43 publications

References 44 publications

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

CD44 inhibition attenuates EGFR signaling and enhances cisplatin sensitivity in human EGFR wild‑type non‑small‑cell lung cancer cells

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

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