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10 pages, 2644 KiB

Open AccessArticle

The Tumour Suppressor Fhit Protein Activates C-Raf Ubiquitination and Degradation in Human Melanoma Cells by Interacting with Hsp90

by Francesco Paduano, Eugenio Gaudio and Francesco Trapasso

Biomedicines 2022, 10(10), 2551; https://doi.org/10.3390/biomedicines10102551 - 13 Oct 2022

Cited by 1 | Viewed by 1611

Abstract

Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is [...] Read more.

Fhit protein expression is reduced in the majority of human tumors; moreover, its restoration both triggers apoptosis of cancer cells and suppresses tumor formation in a large number of preclinical models of cancers. In the following study, we observed that Fhit expression is significantly reduced in human melanoma cells, and their in vivo growth is blocked by a recombinant adenovirus carrying the FHIT gene. Importantly, we found here that Fhit physically interacts with Hsp90. Since Hsp90 is a chaperone with a crucial function in the conformational maturation and stabilization of C-Raf, we also investigated whether Fhit could interfere with the Hsp90/C-Raf protein complex in melanoma. Interestingly, the administration of the Hsp90 inhibitor 17-AAG, in combination with Fhit protein overexpression in melanoma cells, reacts synergistically to increase C-Raf ubiquitination and degradation. These data reveal Hsp90 as a novel interactor of Fhit and suggest that FHIT activity restoration could represent a helpful strategy for suppressing the oncogenic C-Raf pathway in the therapy of human melanoma. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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12 pages, 1354 KiB

Open AccessArticle

Long-Term Response to Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma

by Martina Catalano, Ugo De Giorgi, Marco Maruzzo, Davide Bimbatti, Sebastiano Buti, Giulia Mazzaschi, Giuseppe Procopio, Matteo Santoni, Luca Galli, Raffaele Conca, Laura Doni, Lorenzo Antonuzzo and Giandomenico Roviello

Biomedicines 2022, 10(10), 2444; https://doi.org/10.3390/biomedicines10102444 - 30 Sep 2022

Cited by 3 | Viewed by 1650

Abstract

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients [...] Read more.

Background: Tyrosine kinase inhibitors (TKIs) prolong progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC), some of which may achieve long-term responses. Herein, we report clinical and pathological characteristics of patients who achieved long-term responses during first-line TKI treatment. Methods: Patients receiving TKI as first-line therapy from January 2010 to December 2017 in seven Italian Oncology Centers were reviewed. Sixty-six patients were considered as long-term responders, as they remained progression-free for 36 months or more during TKI treatment. A logistic regression model was performed to evaluate the effect of each clinical-pathological variable on the probability of responding long-term. Results: A total of 335 patients with a median age of 66 years were included in the analysis. The median PFS and overall survival among the long-term responders was 70 and 106 months, respectively. At a landmark PFS analysis performed 36 months after the start of treatment, the median PFS was 34 months. Multivariate analysis from all patients identified previous nephrectomy, Eastern Cooperative Oncology Group Performance Status (ECOG PS) < 1, and lack of liver metastasis as favorable prognostic factors for long-term response. Female gender and lack of liver metastasis positively correlated with long-term responses in favorable-risk-score population, as well as ECOG PS < 1 in intermediate-poor risk score population. Patients Summary: Previous surgery, clinical condition, and lack of liver metastasis may predict long-term responses to tyrosine kinase inhibitors. Conclusions: TKIs can lead to a long-term response in a subset of patients with metastatic RCC. Previous nephrectomy, optimal performance status (ECOG PS = 0), and lack of liver metastasis may predict long-term responses. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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32 pages, 7475 KiB

Open AccessArticle

β-Caryophyllene Counteracts Chemoresistance Induced by Cigarette Smoke in Triple-Negative Breast Cancer MDA-MB-468 Cells

by Antonella Di Sotto, Marco Gullì, Marco Minacori, Romina Mancinelli, Stefania Garzoli, Ester Percaccio, Alessio Incocciati, Donatella Romaniello, Gabriela Mazzanti, Margherita Eufemi and Silvia Di Giacomo

Biomedicines 2022, 10(9), 2257; https://doi.org/10.3390/biomedicines10092257 - 12 Sep 2022

Cited by 3 | Viewed by 1980

Abstract

Exposure to cigarette smoke (CS) has been associated with an increased risk of fatal breast cancers and recurrence, along with chemoresistance and chemotherapy impairment. This strengthens the interest in chemopreventive agents to be exploited both in healthy and oncological subjects to prevent or [...] Read more.

Exposure to cigarette smoke (CS) has been associated with an increased risk of fatal breast cancers and recurrence, along with chemoresistance and chemotherapy impairment. This strengthens the interest in chemopreventive agents to be exploited both in healthy and oncological subjects to prevent or repair CS damage. In the present study, we evaluated the chemopreventive properties of the natural sesquiterpene β-caryophyllene towards the damage induced by cigarette smoke condensate (CSC) in triple negative breast cancer MDA-MB-468 cells. Particularly, we assessed the ability of the sesquiterpene to interfere with the mechanisms exploited by CSC to promote cell survival and chemoresistance, including genomic instability, cell cycle progress, autophagy/apoptosis, cell migration and related pathways. β-Caryophyllene was found to be able to increase the CSC-induced death of MDA-MB-468 cells, likely triggering oxidative stress, cell cycle arrest and apoptosis; moreover, it hindered cell recovery, autophagy activation and cell migration; at last, a marked inhibition of the signal transducer and activator of transcription 3 (STAT3) activation was highlighted: this could represent a key mechanism of the chemoprevention by β-caryophyllene. Although further studies are required to confirm the in vivo efficacy of β-caryophyllene, the present results suggest a novel strategy to reduce the harmful effect of smoke in cancer patients and to improve the survival expectations in breast cancer women. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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16 pages, 759 KiB

Open AccessArticle

Differential Expression of Genes Involved in Metabolism and Immune Response in Diffuse and Intestinal Gastric Cancers, a Pilot Ptudy

by Martine Perrot-Applanat, Cynthia Pimpie, Sophie Vacher, Ivan Bieche, Marc Pocard and Véronique Baud

Biomedicines 2022, 10(2), 240; https://doi.org/10.3390/biomedicines10020240 - 23 Jan 2022

Cited by 4 | Viewed by 3179

Abstract

Gastric cancer (GC) is one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GCs, often associated with poor overall survival, has constantly increased in USA and [...] Read more.

Gastric cancer (GC) is one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GCs, often associated with poor overall survival, has constantly increased in USA and Europe The molecular basis of diffuse GC aggressivity remains unclear. Using mRNA from diffuse and intestinal GC tumor samples of a Western cohort, this study reports the expression level of the immunomodulatory aryl-hydrocarbon receptor (AhR), and genes involved in immune suppression (PD1, PD-L1, PD-L2) and the early steps of tryptophan metabolism (IDO1, IDO2, TDO2). Strongly increased expression of IDO1 (p < 0.001) and PD1 (p < 0.003) was observed in the intestinal sub-type. The highest expression of IDO1 and PDL1 correlated with early clinical stage and absence of lymphatic invasion (×25 p = 0.004, ×3 p = 0.04, respectively). Our results suggest that kynurenine, produced by tryptophan catabolism, and AhR activation play a central role in creating an immunosuppressive environment. Correspondingly, as compared to intestinal GCs, expression levels of IDO1-TDO2 and PD-L1 were less prominent in diffuse GCs which also had less infiltration of immune cells, suggesting an inactive immune response in the advanced diffuse GC. Confirmation of these patterns of gene expression will require a larger cohort of early and advanced stages of diffuse GC samples. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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13 pages, 1371 KiB

Open AccessArticle

Increased Plasma Soluble PD-1 Concentration Correlates with Disease Progression in Patients with Cancer Treated with Anti-PD-1 Antibodies

by Ryotaro Ohkuma, Katsuaki Ieguchi, Makoto Watanabe, Daisuke Takayanagi, Tsubasa Goshima, Rie Onoue, Kazuyuki Hamada, Yutaro Kubota, Atsushi Horiike, Tomoyuki Ishiguro, Yuya Hirasawa, Hirotsugu Ariizumi, Junji Tsurutani, Kiyoshi Yoshimura, Mayumi Tsuji, Yuji Kiuchi, Shinichi Kobayashi, Takuya Tsunoda and Satoshi Wada

Biomedicines 2021, 9(12), 1929; https://doi.org/10.3390/biomedicines9121929 - 16 Dec 2021

Cited by 23 | Viewed by 3916

Abstract

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated [...] Read more.

Immune checkpoint inhibitors (ICIs) confer remarkable therapeutic benefits to patients with various cancers. However, many patients are non-responders or develop resistance following an initial response to ICIs. There are no reliable biomarkers to predict the therapeutic effect of ICIs. Therefore, this study investigated the clinical implications of plasma levels of soluble anti-programmed death-1 (sPD-1) in patients with cancer treated with ICIs. In total, 22 patients (13 with non-small-cell lung carcinoma, 8 with gastric cancer, and 1 with bladder cancer) were evaluated for sPD-1 concentration using enzyme-linked immunosorbent assays for diagnostic and anti-PD-1 antibody analyses. sPD-1 levels were low before the administration of anti-PD-1 antibodies. After two and four cycles of anti-PD-1 antibody therapy, sPD-1 levels significantly increased compared with pretreatment levels (p = 0.0348 vs. 0.0232). We observed an increased rate of change in plasma sPD-1 concentrations after two and four cycles of anti-PD-1 antibody therapy that significantly correlated with tumor size progression (p = 0.024). sPD-1 may be involved in resistance to anti-PD-1 antibody therapy, suggesting that changes in sPD-1 levels can identify primary ICI non-responders early in treatment. Detailed analysis of each cancer type revealed the potential of sPD-1 as a predictive biomarker of response to ICI treatment in patients with cancer. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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24 pages, 5924 KiB

Open AccessArticle

Unraveling Autocrine Signaling Pathways through Metabolic Fingerprinting in Serous Ovarian Cancer Cells

by Ji Hee Ha, Muralidharan Jayaraman, Revathy Nadhan, Srishti Kashyap, Priyabrata Mukherjee, Ciro Isidoro, Yong Sang Song and Danny N. Dhanasekaran

Biomedicines 2021, 9(12), 1927; https://doi.org/10.3390/biomedicines9121927 - 16 Dec 2021

Cited by 8 | Viewed by 3252

Abstract

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established [...] Read more.

Focusing on defining metabolite-based inter-tumoral heterogeneity in ovarian cancer, we investigated the metabolic diversity of a panel of high-grade serous ovarian carcinoma (HGSOC) cell-lines using a metabolomics platform that interrogate 731 compounds. Metabolic fingerprinting followed by 2-dimensional and 3-dimensional principal component analysis established the heterogeneity of the HGSOC cells by clustering them into five distinct metabolic groups compared to the fallopian tube epithelial cell line control. An overall increase in the metabolites associated with aerobic glycolysis and phospholipid metabolism were observed in the majority of the cancer cells. A preponderant increase in the levels of metabolites involved in trans-sulphuration and glutathione synthesis was also observed. More significantly, subsets of HGSOC cells showed an increase in the levels of 5-Hydroxytryptamine, γ-aminobutyrate, or glutamate. Additionally, 5-hydroxytryptamin synthesis inhibitor as well as antagonists of γ-aminobutyrate and glutamate receptors prohibited the proliferation of HGSOC cells, pointing to their potential roles as oncometabolites and ligands for receptor-mediated autocrine signaling in cancer cells. Consistent with this role, 5-Hydroxytryptamine synthesis inhibitor as well as receptor antagonists of γ-aminobutyrate and Glutamate-receptors inhibited the proliferation of HGSOC cells. These antagonists also inhibited the three-dimensional spheroid growth of TYKNU cells, a representative HGSOC cell-line. These results identify 5-HT, GABA, and Glutamate as putative oncometabolites in ovarian cancer metabolic sub-type and point to them as therapeutic targets in a metabolomic fingerprinting-based therapeutic strategy. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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11 pages, 1428 KiB

Open AccessArticle

Optimizing the Schedule of PARP Inhibitors in Combination with ¹⁷⁷Lu-DOTATATE: A Dosimetry Rationale

by Andreas Hallqvist, Johanna Svensson, Linn Hagmarker, Ida Marin, Tobias Rydén, Jean-Mathieu Beauregard and Peter Bernhardt

Biomedicines 2021, 9(11), 1570; https://doi.org/10.3390/biomedicines9111570 - 29 Oct 2021

Cited by 7 | Viewed by 1884

Abstract

¹⁷⁷Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair ¹⁷⁷Lu-induced DNA [...] Read more.

¹⁷⁷Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair ¹⁷⁷Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance ¹⁷⁷Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with ¹⁷⁷Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during ¹⁷⁷Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of ¹⁷⁷Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to ¹⁷⁷Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of ¹⁷⁷Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and ¹⁷⁷Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267). Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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17 pages, 26716 KiB

Open AccessArticle

Poly (ADP-Ribose) Polymerase Inhibitor, ABT888, Improved Cisplatin Effect in Human Oral Cell Carcinoma

by Irene Paterniti, Sarah Adriana Scuderi, Giovanna Casili, Marika Lanza, Marzia Mare, Raffella Giuffrida, Cristina Colarossi, Marco Portelli, Salvatore Cuzzocrea and Emanuela Esposito

Biomedicines 2021, 9(7), 771; https://doi.org/10.3390/biomedicines9070771 - 2 Jul 2021

Cited by 5 | Viewed by 3194

Abstract

Cisplatin is one of the chemotherapeutic drugs used for the management of oral carcinoma, in which combined therapies are estimated to exert superior therapeutic efficacy compared with monotherapy. It is known that poly(ADP-ribosyl)ation is implicated in a multiplicity of cellular activities, such as [...] Read more.

Cisplatin is one of the chemotherapeutic drugs used for the management of oral carcinoma, in which combined therapies are estimated to exert superior therapeutic efficacy compared with monotherapy. It is known that poly(ADP-ribosyl)ation is implicated in a multiplicity of cellular activities, such as DNA repair and cell death. Based on these, PARP inhibitors are used for the treatment of cancers; however, the capacity of PARP inhibitors associated to anti-cancer drugs have not been completely assessed in oral carcinoma. Here, we evaluated the effects of PARPi veliparib (ABT888) in combination with cisplatin on the survival of three human oral cancer cell lines HSC-2, Ca9-22 and CAL27 and we observed the effects of ABT888 alone or in combination with cisplatin on apoptosis and DNA damage repair mechanism. The results obtained showed that ABT888 induces a cytotoxicity effect on cell viability increasing the apoptotic pathway as well as DNA strand break; moreover, our results displayed the effects with cisplatin in a dose-dependent manner. Therefore, our results indicate PARP inhibitors as adjuvants for therapeutic strategy of oral cancer. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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18 pages, 4156 KiB

Open AccessArticle

RABL6A Promotes Pancreatic Neuroendocrine Tumor Angiogenesis and Progression In Vivo

by Chandra K. Maharjan, Shaikamjad Umesalma, Courtney A. Kaemmer, Viviane P. Muniz, Casey Bauchle, Sarah L. Mott, K. D. Zamba, Patrick Breheny, Mariah R. Leidinger, Benjamin W. Darbro, Samuel B. Stephens, David K. Meyerholz and Dawn E. Quelle

Biomedicines 2021, 9(6), 633; https://doi.org/10.3390/biomedicines9060633 - 2 Jun 2021

Cited by 7 | Viewed by 3913

Abstract

Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell [...] Read more.

Pancreatic neuroendocrine tumors (pNETs) are difficult-to-treat neoplasms whose incidence is rising. Greater understanding of pNET pathogenesis is needed to identify new biomarkers and targets for improved therapy. RABL6A, a novel oncogenic GTPase, is highly expressed in patient pNETs and required for pNET cell proliferation and survival in vitro. Here, we investigated the role of RABL6A in pNET progression in vivo using a well-established model of the disease. RIP-Tag2 (RT2) mice develop functional pNETs (insulinomas) due to SV40 large T-antigen expression in pancreatic islet β cells. RABL6A loss in RT2 mice significantly delayed pancreatic tumor formation, reduced tumor angiogenesis and mitoses, and extended survival. Those effects correlated with upregulation of anti-angiogenic p19ARF and downregulation of proangiogenic c-Myc in RABL6A-deficient islets and tumors. Our findings demonstrate that RABL6A is a bona fide oncogenic driver of pNET angiogenesis and development in vivo. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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16 pages, 1598 KiB

Open AccessReview

Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

by Wanglong Qiu, Chia-Yu Kuo, Yu Tian and Gloria H. Su

Biomedicines 2021, 9(7), 821; https://doi.org/10.3390/biomedicines9070821 - 14 Jul 2021

Cited by 5 | Viewed by 6538

Abstract

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, [...] Read more.

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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8 pages, 412 KiB

Open AccessPerspective

Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

by L. Eric Huang

Biomedicines 2022, 10(2), 246; https://doi.org/10.3390/biomedicines10020246 - 24 Jan 2022

Cited by 23 | Viewed by 5576

Abstract

Although hotspot mutations in isocitrate dehydrogenase (IDH) genes are associated with favorable clinical outcomes in glioma, CDKN2A/B homozygous deletion has been identified as an independent predicator of poor prognosis. Accordingly, the 2021 edition of the World Health Organization (WHO) classification of tumors of [...] Read more.

Although hotspot mutations in isocitrate dehydrogenase (IDH) genes are associated with favorable clinical outcomes in glioma, CDKN2A/B homozygous deletion has been identified as an independent predicator of poor prognosis. Accordingly, the 2021 edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) has adopted this molecular feature by upgrading IDH-mutant astrocytoma to CNS WHO grade IV, even in the absence of glioblastoma-specific histological features—necrosis and microvascular proliferation. This new entity of IDH-mutant astrocytoma not only signifies an exception to the generally favorable outcome of IDH-mutant glioma, but also brings into question whether, and, if so, how, CDKN2A/B homozygous deletion overrides the anti-tumor activity of IDH mutation by promoting the proliferation of stem/neural progenitor-like cells. Understanding the mechanism by which IDH mutation requires intact tumor-suppressor genes for conferring favorable outcome may improve therapeutics. Full article

(This article belongs to the Special Issue Feature Papers in Cancer Biology and Therapeutics)

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