Highlights • The role of Notch in EMT has been demonstrated in several cancers. • Notch activates the expression of EMT markers in endothelial and epithelial cells. • Activation of Notch promotes EMT ...and it is associated to chemoresistance in cancer. • Targeting Notch will reverse the EMT process and sensitize tumors to chemotherapy.
Abstract The A2b receptor (A2b R) belongs to the adenosine receptor family. Emerging evidence suggest that A2b R is implicated in tumor progression in some murine tumor models, but the therapeutic ...potential of targeting A2b R in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2b R agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1) and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b+ Gr1+ ) myeloid-derived suppressor cells (MDSCs). Depletion of CD11b+ Gr1+ cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2b R with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b+ Gr1+ cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8+ ) T cells and natural killer T (NKT) cells and increased levels of T helper 1 (Th1)-like cytokines. Adoptive transfer of CD11b+ Gr1+ cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2b R antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.
Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we ...assessed the therapeutic effect of the humanized anti-Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8
T cells into tumors, and enhanced the efficacy of T-cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.
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Targeting Notch to target cancer stem cells Pannuti, Antonio; Foreman, Kimberly; Rizzo, Paola ...
Clinical cancer research,
06/2010, Letnik:
16, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The cellular heterogeneity of neoplasms has been at the center of considerable interest since the "cancer stem cell hypothesis", originally formulated for hematologic malignancies, was extended to ...solid tumors. The origins of cancer "stem" cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency, and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSCs, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC.
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women ...disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor ...receptor (HER2). TNBC constitutes about 15-30 percent of all diagnosed invasive breast cancer cases in the United States. African-American (AA) women have high prevalence of TNBC with worse clinical outcomes than European-American (EA) women. The contributing factors underlying racial disparities have been divided into two major categories based on whether they are related to lifestyle (non-biologic) or unrelated to lifestyle (biologic). Our objective in the present review article was to understand the potential interactions by which these risk factors intersect to drive the initiation and development of the disparities resulting in the aggressive TNBC subtypes in AA women more likely than in EA women. To reach our goal, we conducted literature searches using MEDLINE/PubMed to identify relevant articles published from 2005 to 2019 addressing breast cancer disparities primarily among AA and EA women in the United States. We found that disparities in TNBC may be attributed to racial differences in biological factors, such as tumor heterogeneity, population genetics, somatic genomic mutations, and increased expression of genes in AA breast tumors which have direct link to breast cancer. In addition, a large number of non-biologic factors, including socioeconomic deprivation adversities associated with poverty, social stress, unsafe neighborhoods, lack of healthcare access and pattern of reproductive factors, can promote comorbid diseases such as obesity and diabetes which may adversely contribute to the aggression of TNBC biology in AA women. Further, the biological risk factors directly linked to TNBC in AA women may potentially interact with non-biologic factors to promote a higher prevalence of TNBC, more aggressive biology, and poor survival. The relative contributions of the biologic and non-biologic factors and their potential interactions is essential to our understanding of disproportionately high burden and poor survival rates of AA women with TNBC.
Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal, and postnatal tissue differentiation. Roles for Notch in ...carcinogenesis, the biology of cancer stem cells, tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) have been reported. This review describes the role of Notch in the "stemness" program in cancer cells and in metastases, together with a brief update on the Notch inhibitors currently under investigation in oncology. These agents may be useful in targeting cancer stem cells and to reverse the EMT process.
γ‐Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to ...probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Extending these findings to mammosphere inhibition assays in triple‐negative breast cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ‐secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of γ‐secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ‐secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds.
Synopsis
γ‐Secretase inhibitors (GSIs) have been repurposed to treat various human cancers. Using newly developed γ‐secretase cleavage assays and a breast cancer cell mammosphere inhibition assay, this study demonstrates that four clinical GSIs are neither pharmacologically nor functionally equivalent.
In vitro and cell‐based assays for human NOTCH1–4 proteins enable facile study of γ‐secretase cleavage and the effects of GSIs, as well as establish sites of cleavage.
Dose–response studies with clinical GSIs reveal markedly different pharmacologic properties.
Studies in triple‐negative breast cancer cell lines show that the clinical GSIs are functionally distinct.
Uncertainty remains regarding the properties of a GSI that are associated with potency in the mammosphere inhibition assay, and might be predictive of a therapeutic effect in human cancer.
γ‐Secretase inhibitors (GSIs) have been repurposed to treat various human cancers. Using newly developed γ‐secretase cleavage assays and a breast cancer cell mammosphere inhibition assay, this study demonstrates that four clinical GSIs are neither pharmacologically nor functionally equivalent.
No other tissue in the body undergoes such a vast and extensive growth and remodeling in a relatively short period of time as the primate endometrium. Endometrial integrity is coordinated by ovarian ...hormones, namely, estrogens, progesterone, and the embryonic hormone chorionic gonadotropin (CG). These regulated events modulate the menstrual cycle and decidualization. The Notch family of transmembrane receptors regulate cellular proliferation, differentiation, and apoptosis, cellular processes required to maintain endometrial integrity. In two primate models, the human and the simulated pregnant baboon model, we demonstrated that Notch1 is increased during the window of uterine receptivity, concomitant with CG. Furthermore, CG combined with estrogens and progesterone up-regulate the level of Notch1, whereas progesterone increases the intracellular transcriptionally competent Notch1, which binds in a complex with progesterone receptor. Inhibition of Notch1 prevented decidualization, and alternatively, when decidualization is biochemically recapitulated in vitro, Notch1 is down-regulated. A focused microarray demonstrated that the Notch inhibitor, Numb, dramatically increased when Notch1 decreased during decidualization. We propose that in the endometrium, Notch has a dual role during the window of uterine receptivity. Initially, Notch1 mediates a survival signal in the uterine endometrium in response to CG from the implanting blastocyst and progesterone, so that menstrual sloughing is averted. Subsequently, Notch1 down-regulation may be critical for the transition of stromal fibroblast to decidual cells, which is essential for the establishment of a successful pregnancy.
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