RESUMO
Although resistance is its major obstacle in cancer therapy, trastuzumab is the most successful agent in treating epidermal growth factor receptor 2 positive (HER2 +) breast cancer (BC). Some patients show resistance to trastuzumab, and scientists want to circumvent this problem. This review elaborately discusses possible resistance mechanisms to trastuzumab and introduces mucin 1 (MUC1) as a potential target efficient for overcoming such resistance. MUC1 belongs to the mucin family, playing the oncogenic/mitogenic roles in cancer cells and interacting with several other oncogenic receptors and pathways, such as HER2, ß-catenin, NF-κB, and estrogen receptor (ERα). Besides, it has been established that MUC1- Cytoplasmic Domain (MUC1-CD) accelerates the development of resistance to trastuzumab and that silencing MUC1-C proto-oncogene is associated with increased sensitivity of HER2+ cells to trastuzumab-induced growth inhibitors. We mention why targeting MUC1 can be useful in overcoming trastuzumab resistance in cancer therapy.
RESUMO
As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.
RESUMO
Triple-negative breast cancer (TNBC) is not as prevalent as hormone receptor or HER2-positive breast cancers and all receptor tests come back negative. More importantly, the heterogeneity and complexity of the TNBC on the molecular and clinical levels have limited the successful development of novel therapeutic strategies and led to intrinsic or developed resistance to chemotherapies and new therapeutic agents. Studies have demonstrated deregulation of Wnt/ß-catenin signaling in tumorigenesis which plays decisive roles at the low survival rate of patients and facilitates resistance to currently existing therapies. This review summarizes mechanisms of Wnt/ß-catenin signaling for resistance development in TNBC, the complex interaction between Wnt/ß-catenin signaling, and the transactivated receptor tyrosine kinase (RTK) signaling pathways, lymphocytic infiltration, epithelial-mesenchymal transition (EMT), and induction of metastasis. Such associations and how these pathways interact in the development and progression of cancer have led to the careful analysis and development of new and effective combination therapies without generating significant toxicity and resistance.
RESUMO
VEGF and its receptor family (VEGFR) members have unique signaling transduction system that play significant roles in most pathological processes, such as angiogenesis in tumor growth and metastasis. VEGF-VEGFR complex is a highly specific mitogen for endothelial cells and any de-regulation of the angiogenic balance implicates directly in endothelial cell proliferation and migration. Moreover, it has been shown that overexpressing Mucin 1 (MUC1) on the surface of many tumor cells resulting in upregulation of numerous signaling transduction cascades, such as growth and survival signaling pathways related to RTKs, loss of cell-cell and cell-matrix adhesion, and EMT. It promotes gene transcription of pro-angiogenic proteins such as HIF-1α during periods of oxygen scarcity (hypoxia) to enhance tumor growth and angiogenesis stimulation. In contrast, the cytoplasmic domain of MUC1 (MUC1-C) inhibits apoptosis, which in turn, impresses upon cell fate. Besides, it has been established that reduction in VEGF expression level correlated with silencing MUC1-C level indicating the anti-angiogenic effect of MUC1 downregulation. This review enumerates the role of MUC1-C oncoprotein and VEGF in angiogenesis and metastasis and describes several signaling pathways by which MUC1-C would mediate the pro-angiogenic activities of cancer cells.
RESUMO
Alteration in glycosylation pattern of MUC1 mucin tandem repeats during carcinomas has been shown to negatively affect adhesive properties of malignant cells and enhance tumor invasiveness and metastasis. In addition, MUC1 overexpression is closely interrelated with angiogenesis, making it a great target for immunotherapy. Alongside, easier interaction of nanobodies (single-domain antibodies) with their antigens, compared to conventional antibodies, is usually associated with superior desirable results. Herein, we evaluated the preclinical efficacy of a recombinant nanobody against MUC1 tandem repeats in suppressing tumor growth, angiogenesis, invasion, and metastasis. Expressed nanobody demonstrated specificity only toward MUC1-overexpressing cancer cells and could internalize in cancer cell lines. The IC50 values (the concentration at which the nanobody exerted half of its maximal inhibitory effect) of the anti-MUC1 nanobody against MUC1-positive human cancer cell lines ranged from 1.2 to 14.3 nm. Similar concentrations could also effectively induce apoptosis in MUC1-positive cancer cells but not in normal cells or MUC1-negative human cancer cells. Immunohistochemical staining of spontaneously developed mouse breast tumors prior to in vivo studies confirmed cross-reactivity of nanobody with mouse MUC1 despite large structural dissimilarities between mouse and human MUC1 tandem repeats. In vivo, a dose of 3 µg nanobody per gram of body weight in tumor-bearing mice could attenuate tumor progression and suppress excessive circulating levels of IL-1a, IL-2, IL-10, IL-12, and IL-17A pro-inflammatory cytokines. Also, a significant decline in expression of Ki-67, MMP9, and VEGFR2 biomarkers, as well as vasculogenesis, was evident in immunohistochemically stained tumor sections of anti-MUC1 nanobody-treated mice. In conclusion, the anti-MUC1 tandem repeat nanobody of the present study could effectively overcome tumor growth, invasion, and metastasis.
Assuntos
Proliferação de Células/genética , Neoplasias Mamárias Animais/patologia , Mucina-1/genética , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neovascularização Patológica/genética , Anticorpos de Domínio Único/genética , Sequências de Repetição em Tandem , Animais , Apoptose/genética , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Reações Cruzadas , Citocinas/metabolismo , Feminino , Humanos , Neoplasias Mamárias Animais/irrigação sanguínea , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mucina-1/imunologia , Ligação Proteica , Anticorpos de Domínio Único/imunologiaRESUMO
As an extensively glycosylated transmembrane protein of epithelium, Mucin1 (MUC1) mostly protects cells from tensions induced by external milieu. Physiologically, during stress condition, MUC1 separates into MUC1-N and MUC1-C moieties, resulting in transduction of inward survival signals, essential for maintaining cell's functionality. Recent studies have proposed a significant correlation between MUC1 overexpression and amplification of cancer cell's proliferation and metastasis through modulation of multiple signaling pathways and cell-cell and cell-matrix interactions. It has been shown that MUC1- Cytoplasmic Domain (MUC1-CD) accelerates development of resistance to several anti-cancer therapeutic agents including bortezomib, trastuzumab and tamoxifen. Furthermore, MUC1-CD is also involved in promoting expression of multi drug resistance (MDR) genes and finally, silencing MUC1 expression was together with resensitization of human epidermal growth factor receptor 2 positive (HER2+) and/or estrogen receptor (ER+) positive breast cancer cells to bortezomib, trastuzumab and tamoxifen respectively. In this review, we briefly describe the role of MUC1 proto-oncogene in cancer cell's survival, tumor progression and metastasis and then continue with mentioning the mechanisms through which MUC1 induce resistance to various currently existing therapeutic agents in market including bortezomib, trastuzumab and tamoxifen.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Mucina-1/metabolismo , Neoplasias/tratamento farmacológico , Tamoxifeno/uso terapêutico , Trastuzumab/uso terapêutico , Antineoplásicos Hormonais/metabolismo , Antineoplásicos Imunológicos/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Neoplasias/metabolismo , Proto-Oncogene Mas , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/metabolismo , Trastuzumab/metabolismoRESUMO
OBJECTIVES: Monoclonal antibody-based of cancer therapy has been considered as one of the most successful therapeutic strategies for both haematologic malignancies and solid tumours in the last two decades. Epidermal growth factor receptor (EGFR) family signalling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Hence, anti-EGFR family mAbs is one of the most promising approaches in cancer therapy. KEY FINDINGS: Here, recent advances in anti-EGFR mAb including approved or successfully tested in preclinical and clinical studies have been reviewed. Although we focus on monoclonal antibodies against the EGF receptor, but the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy, to some extend the resistance to existing anti-EGFR therapies and some therapeutic strategies to overcome resistance such as combination of mAbs on different pathways are briefly discussed as well. SUMMARY: The EGFR family receptors, is considered as an attractive target for mAb development to inhibit their consecutive activities in tumour growth and resistance. However, due to resistance mechanisms, the combination therapies may become a good candidate for targeting EGFR family receptors.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Animais , HumanosRESUMO
INTRODUCTION: Tamoxifen, as an essential therapeutic tool in the treatment of estrogen receptor-positive breast cancer, has been available for the past three decades and is currently being utilized as a chemo-preventive agent for patients at high risk for breast carcinoma. However, the induction of chemo-resistance during therapy has indicated a significant challenge with regards to this agent. Areas covered: This review enumerates the role of MUC1-C proto-oncogene in tamoxifen resistance and describes a number of signaling pathways by which MUC1-C would mediate the development of resistance. Finally, recent clinical studies conducted on the magnitude of MUC1 in inducing tamoxifen resistance are described. Expert commentary: Mucin 1, or MUC1, is aberrantly overexpressed on the entire tumor cell surface of most human cancers. Thus, it may result in the upregulation of several signaling pathways, such as growth cascades related to receptor tyrosine kinases (RTK), ß-catenin and E-cadherin, as well as promoting gene transcription of Ras-related protein Rab-31 in order to mediate tumor growth control in response to tamoxifen. On the contrary, MUC1 suppresses apoptotic events, which in turn impresses upon cell fate. Also, it has been demonstrated that silencing MUC1-C proto-oncogene is associated with increased sensitivity to tamoxifen-induced growth inhibitors.