Targeting Head and Neck Cancer Stem Cells: Current Advances and Future Challenges.
ABSTRACT: Cancer stem cells (CSCs), or tumor-initiating cells, comprise a subset of tumor cells with demonstrated ability for tumor growth, invasion, metastasis, and resistance to chemotherapy and radiation. Targeting of CSCs remains an attractive yet elusive therapeutic option, with the goal of increasing specificity and effectiveness in tumor eradication, as well as decreasing off-target or systemic toxicity. Research into further characterization and targeted therapy toward head and neck CSCs is an active and rapidly evolving field. This review discusses the current state of research into therapy against head and neck CSCs and future directions for targeted therapy.
Project description:Cancer stem cells (CSCs) have been identified as a little population of cancer cells, which have features as the same as the cells normal stem cells. There is enough knowledge of the CSCs responsibility for metastasis, medicine resistance, and cancer outbreak. Therefore, CSCs control possibly provides an efficient treatment intervention inhibiting tumor growth and invasion. In spite of the significance of targeting CSCs in treating cancer, few study comprehensively explored the nature of oral CSCs. It has been showed that oral CSCs are able to contribute to oral cancer progression though activation/inhibition a sequences of cellular and molecular pathways (microRNA network, histone modifications and calcium regulation). Hence, more understanding about the properties of oral cancers and their behaviors will help us to develop new therapeutic platforms. Head and neck CSCs remain a viable and intriguing option for targeted therapy. Multiple investigations suggested the major contribution of the CSCs to the metastasis, tumorigenesis, and resistance to the new therapeutic regimes. Therefore, experts in the field are examining the encouraging targeted therapeutic choices. In spite of the advancements, there are not enough information in this area and thus a magic bullet for targeting and eliminating the CSCs deviated us. Hence, additional investigations on the combined therapies against the head and neck CSCs could offer considerable achievements. The present research is a review of the recent information on oral CSCs, and focused on current advancements in new signaling pathways contributed to their stemness regulation. Moreover, we highlighted various therapeutic approaches against oral CSCs.
Project description:Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC.
Project description:Integrin ?4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor-draining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4-targeted immunotherapy reduced not only the number of ITGB4high CSCs in residual 4T1 and SCC7 tumors but also their tumor-initiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy.Significance: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.
Project description:There is increasing evidence that the growth and spread of cancers is driven by a small subpopulation of cancer stem cells (CSCs)--the only cells that are capable of long-term self-renewal and generation of the phenotypically diverse tumor cell population. CSCs have been identified and isolated in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). The concept of cancer stem cells may have profound implications for our understanding of tumor biology and for the design of novel treatments targeted toward these cells. The present review is an attempt to conceptualize the role of CSCs in HNSCC--its implication in tumorigenesis and the possible additional approach in current treatment strategies.
Project description:Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world. HNSCC remains difficult to treat, and despite advances in treatment, overall survival rate has modestly improved over the past several years. Poor survival rate is attributed to high frequency of local recurrence and distant metastasis. Cancer stem-like cells (CSCs) have been implicated in tumor recurrence and confer resistance to anti-cancer therapy treatment. In this study, we have characterized genes that are modulated in HNSCC-CSCs and can be targeted in future as potential therapeutics. CSCs were isolated from HNSCC cells (oralspheres) and examined for tumorigenicity in immunodeficient mice. We observed aggressive tumor growth with oralspheres as compared to parental cells. The CSC-derived tumors were grossly extremely vascularized and expressed VEGFR1. We next analyzed the molecular determinant of oralspheres. In addition to CD133 and Nanog, we observed significant higher expression of Notch1 protein in the oralspheres. There was differential expression of angiogenesis and invasive marker genes such as angiopoietin1, integrin β3, MMP9 and THBS1. Interestingly, c-Fos was upregulated in oralspheres as compared to parental cells. Our observations suggest that understanding the molecular determinant of oralspheres will help in developing future therapeutic modalities against treatment resistant HNSCC.
Project description:The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated ?H2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.
Project description:Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. SIGNIFICANCE: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.
Project description:Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. Despite advances in the treatment management, locally advanced disease has a poor prognosis, with a 5-year survival rate of approximately 50%. The growth of HNSCC is maintained by a population of cancer stem cells (CSCs) which possess unlimited self-renewal potential and induce tumor regrowth if not completely eliminated by therapy. The population of CSCs is not only a promising target for tumor treatment, but also an important biomarker to identify the patients at risk for therapeutic failure and disease progression. This review aims to provide an overview of the recent pre-clinical and clinical studies on the biology and potential therapeutic implications of HNSCC stem cells.
Project description:Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Cancer stem cells are responsible for the development of tumor cell heterogeneity, a key feature for resistance to anticancer treatments including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Furthermore, minimal residual disease, the major cause of cancer recurrence and metastasis, is enriched in CSCs. Cancer stem cells also possess the property of "robustness", which encompasses several characteristics including a slow cell cycle, the ability to detoxify or mediate the efflux of cytotoxic agents, resistance to oxidative stress, and a rapid response to DNA damage, all of which contribute to the development of therapeutic resistance. The identification of mechanisms underlying such characteristics and the development of novel approaches to target them will be required for the therapeutic elimination of CSCs and the complete eradication of tumors. In this review, we focus on two prospective therapeutic approaches that target CSCs with the aim of disrupting their quiescence or redox defense capability.
Project description:Receptor heterogeneity in cancer is a major limitation of molecular targeting for cancer therapeutics. Single-receptor-targeted treatment exerts selection pressures that result in treatment escape for low-receptor-expressing tumor subpopulations. To overcome this potential for heterogeneity-driven resistance to molecular targeted photodynamic therapy (PDT), we present for the first time a triple-receptor-targeted photoimmuno-nanoconjugate (TR-PIN) platform. TR-PIN functionalization with cetuximab, holo-transferrin, and trastuzumab conferred specificity for epidermal growth factor receptor (EGFR), transferrin receptor (TfR), and human epidermal growth factor receptor 2 (HER-2), respectively. The TR-PINs exhibited up to a 24-fold improvement in cancer cell binding compared with EGFR-specific cetuximab-targeted PINs (Cet-PINs) in low-EGFR-expressing cell lines. Photodestruction using TR-PINs was significantly higher than the monotargeted Cet-PINs in heterocellular 3D in vitro models of heterogeneous pancreatic ductal adenocarcinoma (PDAC; MIA PaCa-2 cells) and heterogeneous head and neck squamous cell carcinoma (HNSCC, SCC9 cells) containing low-EGFR-expressing T47D (high TfR) or SKOV-3 (high HER-2) cells. Through their capacity for multiple tumor target recognition, TR-PINs can serve as a unique and amenable platform for the effective photodynamic eradication of diverse tumor subpopulations in heterogeneous cancers to mitigate escape for more complete and durable treatment responses.