Methods for Overcoming Chemoresistance in Head and Neck Squamous Cell Carcinoma: Keeping the Focus on Cancer Stem Cells, a Systematic Review.

According to the "cancer stem cell" (CSCs) theory, tumors are a diverse and expanding group of malignant cells that originate from a small number of CSCs. Despite treatment, these cells can still become active and proliferate, which can result in distant metastasis and local recurrences. A new paradigm in cancer treatment involves targeting both CSCs and the cancer cells in a tumor. This review aims to examine the literature on methods published to overcome chemoresistance due to the presence of CSCs in head and neck cancers. The review was registered with PROSPERO (ID# CRD42024512809). After Pub Med, Scopus, and WoS database searches, 31 relevant articles on oral squamous cell carcinoma (OSCC) were selected. Compounds that increased chemosensitivity by targeting CSCs in head and neck squamous cell carcinoma (HNSCC) were divided into (1) natural products, (2) adjuvant molecules to traditional chemotherapy, and (3) CSCs targeting patient-specific fresh biopsies for functional precision medicine.

CD103 blockade impair anti-CTLA-4 immunotherapy in oral cancer.

OBJECTIVES: CD103+CD8+T cells is a subtype of T cells with excellent tumor killing ability and it could response to immune checkpoint blockade therapy in several types of cancer, but the phenotype, role and molecular mechanism CD103+CD8+T cells in the OSCC still unclear. MATERIALS AND METHODS: The distribution and phenotype of CD103+CD8+T cells were investigated by performing multiplexed immunohistochemistry on human OSCC tissue microarray and flow cytometric analysis of fresh OSCC tumor-infiltrating lymphocytes (TILs). By in vivo use of anti-CD103 monoclonal antibody (mAb) in the 4MOSC1 tumor-bearing mouse model, CD103+CD8+T cell infiltration and cytotoxicity was clarified. RESULTS: The majority of CD8+T cells in both human and animal OSCC intra-tumoral region were CD103+CD8+T cells with high expression levels of cytotoxic molecules, which can be impaired by CD103 blockade. In addition, combined use of anti-CD103 mAb with anti-CTLA-4 mAb displayed impaired immune checkpoint blockade therapy efficiency. CONCLUSION: CD103+CD8+T cells are the major intra-tumoral subset of CD8+T cells in both animal and human OSCC, and that CD103+CD8+T cells demonstrate remarkable tumor-infiltrating and tumor-killing properties, thereby CD103+CD8+T cells may critical for anti-CTLA-4 immunotherapy in OSCC.

Regorafenib enhances antitumor immune efficacy of anti-PD-L1 immunotherapy on oral squamous cell carcinoma.

Oral squamous cells carcinoma (OSCC) is the most common oral malignancy that majorly originated from oral cavity. Though the prognostic and predictive value of targeting checkpoint molecules has been reported on OSCC, the treatment efficacy of monotherapy is remaining limited. Several studies suggested that multikinase inhibitors may show potential to facilitate anti-PD-L1-induced anti-tumor immunity. Regorafenib, an oral multikinase inhibitor has been approved by FDA for various types of cancer treatment. Here, we aim to identify whether regorafenib may boost anti-tumor immunity of anti-PD-L1 in MOC1-bearing OSCC animal model. The alteration of immune cells such as M1/M2-like macrophages (MΦ), cytotoxicity T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) after combination of anti-PD-L1 and regorafenib was validated by flow cytometry and immunohistochemistry staining. The combination index analysis (CI=0.89) supported that regorafenib effectively induce anti-OSCC efficacy of anti-PD-L1. Combination of anti-PD-L1 and regorafenib may not only trigger the polarization of M1-like MΦ (CD11b+CD86+) in mice bone marrow (BM) and spleen (SP), but also induce the accumulation and function of CD8+ T cells in tumor-draining lymph node (TDLN) and tumor. In addition, immunosuppressive related cells (MDSCs and Treg) and factors were all decreased by combination therapy in BM, SP and tumor. In sum, regorafenib may improve anti-OSCC efficacy of anti-PD-L1 through systemically and locally upregulating the immunostimulation immunity and suppressing immunosuppression immunity.

CD133 Role in Oral Carcinogenesis.

OBJECTIVE: to investigate CD133 immunoexpression, cancer stem cells marker, in oral epithelial dysplasias (OEDs) and oral squamous cells carcinomas (OSCCs) and understandits possible involvement in the malignant transformation process of these lesions and to better elucidate their biological behavior. MATERIAL AND METHODS: Tissue samples of 15 cases of OSCCs and 15 OEDs were subjected to CD133 antibody immunohistochemistry reactions. The analysis used quantitative parameters (number of immunostained cells regardless of immunostaining sublocations). RESULTS: All samples of OSCCs and OEDs showed positive immunostaining, with no significant difference between these groups (p = 0.283). We did not observe statistical difference between the degree of dysplasia and the amount of CD133+ cells (p = 0.899). CD133 immunoexpression showed no association with the OEDs and OSCCs sites. It was observed that nuclear and cytoplasmic immunostaining was more evident with the progression of the malignant process. CONCLUSION: It is suggested that the CD133 cellular localization together with the histopathological criteria of OEDs classification can contribute to provide more concrete indications about the oral carcinogenesis process.

ASCT2 overexpression is associated with poor survival of OSCC patients and ASCT2 knockdown inhibited growth of glutamine-addicted OSCC cells.

BACKGROUND: Alanine-serine-cysteine transporter 2 (ASCT2), a major glutamine transporter, is essential for cell growth and tumor development in a variety of cancers. However, the clinicopathological significance and pathological role of ASCT2 in OSCC (oral squamous cell carcinoma) lesions remain unclear. METHODS: Sections from 89 OSCC patients and 10 paracancerous tissue controls were stained by immunohistochemistry (IHC) to detect the expression of ASCT2, glutaminase, and Ki-67. Survival analysis was carried out to determine the predictive value of ASCT2 expression using the log-rank test. Moreover, the critical role of ASCT2 in tumor growth was determined by a series of in vitro and in vivo assays. Cell Counting Kit-8 (CCK8), Western Blotting (WB), Reactive Oxygen Species (ROS), and Glutathione (GSH) detection were applied to explore the molecular mechanism of ASCT2 involvement in tumor development. RESULTS: In OSCC lesions, ASCT2 expression was significantly increased and associated with cell proliferation index (Ki-67) and GLS expression. Moreover, survival analysis showed that OSCC patients with high ASCT2 expression had lower overall survival (P = 0.0365). In OSCC cell lines, the high level of ASCT2 was inherent and related to the glutamine addiction of tumor cells. In vitro and in vivo functional experiments revealed that targeted silencing of ASCT2 can effectively inhibit OSCC cell proliferation and tumor growth. Mechanistically, targeting ASCT2 knockdown reduced glutamine uptake and intracellular GSH levels, which contribute to the accumulation of ROS and induce apoptosis in OSCC cells. CONCLUSION: ASCT2 is a significant factor for predicting overall survival in patients with OSCC, and targeting ASCT2 to inhibit glutamine metabolism may be a promising strategy for OSCC treatment.

Meloxicam Inhibit the Growth of Oral Squamous Cell Carcinoma Induced by Benzopyrenes

@#Introduction: Meloxicam is a NSAID which able to inhibit the cyclooxygenase 2 (COX-2). The purpose of this research is to explain the effect of Meloxicam in inhibit the growth of oral squamous cell carcinoma (OSCC) induced by benzopyrenes. The apoptosis and proliferation of OSCC, the p53, Ras and COX-2 expression used as indicator. Methods: male mice were induced by benzopyrene 10 mg/kg body weight was given topically on buccal mucosa 2 times a week for 4 weeks for induced the OSCC. Meloxicam was given orally with 3 different doses was 50mg/kg, 100mg/kg, and 200mg/kg.b.w given once a day for 60 days. The control groups were given with CMC-1% 0.1ml/10g body weight. The buccal mucosa then biopsy and staining with immunohistochemistry to analyzed the p53, Ras, COX-2 expression, apoptosis and proliferation of OSCC. Results: The increase of Meloxicam dose is proportional to the increase in wild p53 expression and apoptosis, and inversely proportional to the expression of mutant race, cox-2 and the proliferation of OSCC. Conclusion: Meloxicam able to inhibit the growth of OSCC induced by benzopyrenes.

Risk Factors Analysis of Pathologically Confirmed Cervical Lymph Nodes Metastasis in Oral Squamous Cell Carcinoma Patients with Clinically Negative Cervical Lymph Node: Results from a Cancer Center of Central China.

Objective: To explore the risk factors of cervical lymph node metastasis in oral squamous cell carcinoma (OSCC) patients with clinical negative cervical lymph nodes(cN0) and provide a reference for clinical treatment. Methods: The clinical data of 161 OSCC patients with cN0 were retrospectively analyzed. All patients underwent extended primary resection combined with cervical lymph node dissection. The level and number of cervical lymph node metastasis were confirmed by postoperative pathology. The risk factors of cervical lymph node metastasis in patients were analyzed by univariate and multivariate Logistic regression analysis. Results: Thirty-one out of 161 cases (19%) were confirmed cervical lymph node metastasis. Among them, there were 28 cases of lymph node metastasis in one cervical level and 3 cases in two cervical levels. A total of 42 positive lymph nodes were detected in 34 cervical levels. The level number of positive areas in the IA, IB, IIA, IIB, III, IV and V levels was 2, 15, 12, 1, 4,0, and 0, respectively. The corresponding regional metastasis rates were 5.9%, 44.1%, 35.3%, 2.9%, 11.8%, 0% and 0%, respectively. The number of positive lymph node metastases in the corresponding levels were 2, 17, 17, 1, 5, 0, and 0 respectively. Univariate analysis showed that gender, age, lesion location, T stage, and perineural invasion/lymphvascular invasion (PNI/PVI) had no significant effect on cervical lymph node metastasis (P>0.05). The growth pattern, degree of differentiation, depth of invasion, neutrophil/lymphocyte ratio (NLR) and the short/long axis diameter ratio (S/L ratio) of lymph nodes were important factors influencing the cervical lymph node metastasis in cN0 OSCC patients (P<0.05). Multivariate Logistic regression analysis indicated that the growth pattern, degree of differentiation, depth of invasion, NLR, and the S/L ratio of lymph nodes were independent risk factors for cervical lymph node metastasis (P<0.05). Conclusion: The growth pattern, degree of differentiation, depth of invasion, neutrophil/lymphocyte ratio, and the short/long axis diameter ratio of lymph nodes were the independent risk factors for pathological cervical lymph node metastasis in oral squamous cell carcinoma patients with cN0. If patients with the above risk factors receive nonstandard radical neck dissection or no dissection, it may be necessary for them to receive the corresponding regional postoperative radiotherapy.

Misdiagnosis of lip squamous cell carcinoma

Introduction : Lip squamous cell carcinoma is a malignant lesion of aggressive behavior, which must be recognized by health professionals to prevent damage to patient's health.Objective:To present incisional biopsy importance as an effective clinical approach for the diagnosis of lip squamous cell carcinoma and actinic cheilitis malignancy as well as the professional's lack of knowledge on these two diseases. Case report:The patient was under medical treatment due to be positive for human immunodeficiency virus and because of the actinic cheilitis on lower lip. Because the patient did not observe the labial lesion regression, he searched for the School of Dentistry of the University Center of the Educational Foundation of Barretos, where he underwent biopsy. This procedure confirmed the diagnosis of lip squamous cell carcinoma. The patient was referred for treatment in a specialized cancer center and has been living with the cancer consequences. Conclusion:The physician and dentist must be aware of the main clinical features of lip squamous cell carcinoma so that they can establish its correct diagnosis and early treatment.