RESUMO
Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Terapia Combinada , Imunoterapia , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
The association between the pretreatment body mass index (BMI) and oral squamous cell carcinoma (SCC) outcomes is controversial. We aimed to examine the association between BMI and cause-specific mortality due to cancer of the oral cavity and patterns of failure that correlate with increased mortality. We enrolled 2,023 East Asian patients in this multicenter cohort study. We used the cumulative incidence competing risks method and the Fine-Gray model to analyze factors associated with cause-specific mortality, local recurrence, regional metastasis, and distant metastasis as first events. The median follow-up period was 62 mo. The 5-year cause-specific mortality for patients with underweight was 25.7%, which was significantly higher than that for patients with normal weight (12.7%, P < 0.0001). The multivariate model revealed that underweight was an independent risk factor for cause-specific mortality and regional metastasis (P < 0.05). Moreover, patients with underweight displayed a 51% and 55% increased risk of cause-specific mortality and regional metastasis, respectively, compared with their normal weight counterparts. Local recurrence was not associated with the BMI categories; however, the incidence of distant metastasis inversely decreased with BMI value. In summary, being underweight at diagnosis should be considered a high-risk mortality factor for oral SCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/patologia , Índice de Massa Corporal , Magreza/complicações , Estudos de Coortes , Causas de Morte , Fatores de Risco , Redução de Peso , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estudos RetrospectivosRESUMO
Transforming growth factor ß (TGF-ß) increases epithelial cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). TGF-ß also inhibits cell proliferation by inducing G1 phase cell-cycle arrest. However, the correlation between these tumor-promoting and -suppressing effects remains unclear. Here, we show that TGF-ß confers higher motility and metastatic ability to oral cancer cells in G1 phase. Mechanistically, keratin-associated protein 2-3 (KRTAP2-3) is a regulator of these dual effects of TGF-ß, and its expression is correlated with tumor progression in patients with head and neck cancer and migratory and metastatic potentials of oral cancer cells. Furthermore, single-cell RNA sequencing reveals that TGF-ß generates two populations of mesenchymal cancer cells with differential cell-cycle status through two distinctive EMT pathways mediated by Slug/HMGA2 and KRTAP2-3. Thus, TGF-ß-induced KRTAP2-3 orchestrates cancer cell proliferation and migration by inducing EMT, suggesting motile cancer cells arrested in G1 phase as a target to suppress metastasis.
Assuntos
Neoplasias Bucais , Fator de Crescimento Transformador beta , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinas/metabolismo , Neoplasias Bucais/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factorß (TGFß) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelialmesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGFß isoforms, TGFß1, TGFß2 and TGFß3, all of which engage in protumorigenic activities by activating SMAD signaling pathways. All TGFß isoforms activate signaling pathways by binding to their TGFß type I (TßRI) and type II (TßRII) receptors. Thus, effective targeting of all TGFß isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TßRI and/or TßRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TßRI and TßRII (TßRITßRIIFc) effectively trapped all TGFß isoforms. Conversely, TßRIIFc chimeric receptor, that comprises TßRII only, was able to interact with TGFß1 and TGFß3 isoforms, but not with TGFß2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TßRITßRIIFc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGFß isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TßRIIFc chimeric receptor inhibited the EMT program induced by TGFß1 and TGFß3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TßRITßRIIFc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGFß signals that affect various components of the TME may result in the development of effective antimelanoma agents.
Assuntos
Melanoma/metabolismo , Receptores Fc/metabolismo , Neoplasias Cutâneas/metabolismo , Fator de Crescimento Transformador beta1/biossíntese , Animais , Proliferação de Células , Citocinas/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal , Células HEK293 , Humanos , Imunoglobulina G/química , Melanoma/patologia , Melanoma Experimental , Camundongos , Ligação Proteica , Isoformas de Proteínas , Receptores de Antígenos Quiméricos/química , Transdução de Sinais , Neoplasias Cutâneas/patologia , Proteínas Smad/metabolismo , Microambiente TumoralRESUMO
Three-dimensional (3D) cell culture systems have been used to obtain multicellular spheroidal cell aggregates, or spheroids, from cancer cells. However, it is difficult to efficiently prepare large tumor-derived spheroids from cancer cells. To circumvent this problem, we here used a tool equipped with removal membrane, called Spheroid Catch, for the selection and enrichment of large-sized and/or size-matched spheroids from human squamous cell carcinoma (SAS cells) without loss of recovery. After a five-round process of selection and enrichment, we successfully isolated a subpopulation of SAS cells with augmented spheroid-forming capability, named eSAS: the efficiency of spheroid formation is 28.5% (eSAS) vs 16.8% (parental SAS). Notably, we found that some of eSAS cells survived after exposure of high doses of cisplatin in 3D culture. Moreover, orthotopic implantation by injecting eSAS cells into the tongues of nude mice showed reduced survival rate and increased tumor growth compared with those of nude mice injected with SAS cells. These results suggest that spheroids exhibiting properties of higher spheroid forming capacity can be efficiently collected by using Spheroid Catch. Indeed, genome-wide cDNA microarray and western blot analyses demonstrated higher mRNA and protein levels of hedgehog acyltransferase (HHAT), which is associated with stem maintenance in cell carcinoma by catalysing the N-palmitoylation of Hedgehog proteins, in eSAS cells than in SAS cells. We propose that Spheroid Catch could be useful for the study of spheroids, and potentially organoids, in the basic and clinical sciences, as an alternative method to other type of cell strainers.