Induction of CD44 Variant 9-Expressing Cancer Stem Cells Might Attenuate the Efficacy of Chemoradioselection and Worsens the Prognosis of Patients with Advanced Head and Neck Cancer

Abstract

BackgroundAt our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30–40 Gy concurrent chemoradiotherapy (CCRT). Patients with a favorable response (i.e., chemoradioselected; CRS) have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS). Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC) marker, CD44 variant 9 (CD44v9), with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC).Materials and MethodsThrough a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies.ResultsThe intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008) worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9), CD44v9 positivity (HR: 3.145, 95% CI: 1.235–8.008, P = 0.0163) was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054–9.060, P = 0.0228). Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04) worse than the CD44v9-non-induced group.ConclusionsCCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of chemoradioselection and consequent organ preservation and survival.

Sulfasalazine could modulate the CD44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer

“…In the present study, we examined 63 MIBC patients who under- tissue samples has also been reported in various cancers, such as gastric, 24 hepatocellular, 25 and head and neck cancers. 26 In the field of urothelial cancer, Miyake et al 12 The initial finding of SSZ as a potent inhibitor of xCT was investigated in lymphoma cells 14 and increasing numbers of studies reported the anticancer effects of SSZ in various cancers, such as glioma, 27 prostate cancer, 28 and pancreatic cancer. 16 Furthermore, SSZ was shown to enhance the therapeutic efficacy of chemotherapies.…”

Preoperative assessment of CD44‐mediated depth of invasion as predictor of occult metastases in early oral squamous cell carcinoma

“…The monoclonal antibody used in our study binds to the epitope 1 of CD44, which is expressed in the standard CD44 isoform as well as in his alternative splicing variants . A recent study demonstrated that both populations have important implications for stem cell‐like potential, resulting in poorer outcome and therapeutic resistance . Mechanistically, CD44 expression promotes glutathione production and regulation of redox status, thereby protecting CSCs from reactive oxygen species …”

“…Furthermore, enrichment in EMT sustains propagation of cells with stem cell‐like characteristics within a tumor . These two processes overlap and share common signaling pathways, such as Notch, BMI‐1, Hedgehog, and Wnt . Activation of these pathways results in increased expression of several proteins, which can in turn be used as surrogate markers to tag cancer stem‐like cell (CSC) potential.…”

“…14,15 These two processes overlap and share common signaling pathways, such as Notch, BMI-1, Hedgehog, and Wnt. [16][17][18][19][20] Activation of these pathways results in increased expression of several proteins, which can in turn be used as surrogate markers to tag cancer stem-like cell (CSC) potential. A key marker for EMT/CSC is thought to be the transmembranous CD44 protein, which is the principal cell surface receptor for hyaluronic acid (HA).…”

<b>CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected </b><b>tissues </b>

“…Such findings suggest that CD44v9-positive cells have a specific function in protecting against ROS, and contribute to features of cancer stem cells. In addition, expression of CD44v9 in tumor tissues has also been associated with tumor recurrence and prognosis in patients with several types of cancer (4,19,20,31,33). Recently, expression levels of CD44v9 in early gastric cancer have also been shown to correlate positively with the risk of recurrence in patients who underwent endoscopic submucosal dissection (21).…”