Cancers

24 pages, 4356 KiB

Open AccessArticle

Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

by Matilda Munksgaard Thorén, Katarzyna Chmielarska Masoumi, Cecilia Krona, Xiaoli Huang, Soumi Kundu, Linnéa Schmidt, Karin Forsberg-Nilsson, Marcus Floyd Keep, Elisabet Englund, Sven Nelander, Bo Holmqvist and Evy Lundgren-Åkerlund

Cancers 2019, 11(4), 587; https://doi.org/10.3390/cancers11040587 - 25 Apr 2019

Cited by 30 | Viewed by 6484

Abstract

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 [...] Read more.

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM. Full article

(This article belongs to the Special Issue The Role of Integrins in Cancer)

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15 pages, 1003 KiB

Open AccessArticle

Chromogranin A in the Laboratory Diagnosis of Pheochromocytoma and Paraganglioma

by Radovan Bílek, Petr Vlček, Libor Šafařík, David Michalský, Květoslav Novák, Jaroslava Dušková, Eliška Václavíková, Jiří Widimský, Jr. and Tomáš Zelinka

Cancers 2019, 11(4), 586; https://doi.org/10.3390/cancers11040586 - 25 Apr 2019

Cited by 41 | Viewed by 5791

Abstract

This work discusses the clinical performance of chromogranin A (CGA), a commonly measured marker in neuroendocrine neoplasms, for the diagnosis of pheochromocytoma/paraganglioma (PPGL). Plasma CGA (cut-off value 150 µg/L) was determined by an immunoradiometric assay. Free metanephrine (cut-off value 100 ng/L) and normetanephrine [...] Read more.

This work discusses the clinical performance of chromogranin A (CGA), a commonly measured marker in neuroendocrine neoplasms, for the diagnosis of pheochromocytoma/paraganglioma (PPGL). Plasma CGA (cut-off value 150 µg/L) was determined by an immunoradiometric assay. Free metanephrine (cut-off value 100 ng/L) and normetanephrine (cut-off value 170 ng/L) were determined by radioimmunoassay. Blood samples were collected from PPGL patients preoperatively, one week, six months, one year and two years after adrenal gland surgery. The control patients not diagnosed with PPGL suffered from adrenal problems or from MEN2 and thyroid carcinoma. The clinical sensitivity in the PPGL group of patients (n = 71) based on CGA is 90% and is below the clinical sensitivity determined by metanephrines (97%). The clinical specificity based on all plasma CGA values after surgery (n = 98) is 99% and is the same for metanephrines assays. The clinical specificity of CGA in the control group (n = 85) was 92% or 99% using metanephrines tests. We can conclude that plasma CGA can serve as an appropriate complement to metanephrines assays in laboratory diagnosis of PPGL patients. CGA is elevated in PPGLs, as well as in other neuroendocrine or non-neuroendocrine neoplasia and under clinical conditions increasing adrenergic activity. Full article

(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))

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19 pages, 8533 KiB

Open AccessArticle

Deletions of Chromosome 7q Affect Nuclear Organization and HLXB9Gene Expression in Hematological Disorders

by Concetta Federico, Temitayo Owoka, Denise Ragusa, Valentina Sturiale, Domenica Caponnetto, Claudia Giovanna Leotta, Francesca Bruno, Helen A. Foster, Silvia Rigamonti, Giovanni Giudici, Giovanni Cazzaniga, Joanna M. Bridger, Cristina Sisu, Salvatore Saccone and Sabrina Tosi

Cancers 2019, 11(4), 585; https://doi.org/10.3390/cancers11040585 - 25 Apr 2019

Cited by 11 | Viewed by 5183

Abstract

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of [...] Read more.

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods. Full article

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14 pages, 1575 KiB

Open AccessArticle

Differential Activation of ERK Signaling in HPV-Related Oropharyngeal Squamous Cell Carcinoma

by Chao Rong, Marie Muller, Christa Flechtenmacher, Dana Holzinger, Gerhard Dyckhoff, Olcay Cem Bulut, Dominik Horn, Peter Plinkert, Jochen Hess and Annette Affolter

Cancers 2019, 11(4), 584; https://doi.org/10.3390/cancers11040584 - 25 Apr 2019

Cited by 14 | Viewed by 4458

Abstract

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various [...] Read more.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling. Full article

(This article belongs to the Special Issue Protein Kinases and Cancers)

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13 pages, 1145 KiB

Open AccessArticle

Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients

by Martijn van der Heijden, Monique C. de Jong, Caroline V. M. Verhagen, Reinout H. de Roest, Sebastian Sanduleanu, Frank Hoebers, C. René Leemans, Ruud H. Brakenhoff, Conchita Vens, Marcel Verheij and Michiel W. M. van den Brekel

Cancers 2019, 11(4), 583; https://doi.org/10.3390/cancers11040583 - 25 Apr 2019

Cited by 15 | Viewed by 3845

Abstract

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four [...] Read more.

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four clinical hypoxia profiles were compared to in vitro acute and chronic hypoxia profiles. Chronic and acute hypoxia profiles were tested for their association to outcome using Cox proportional hazard analyses. In an initial set of 224 patients, scores of the four clinical hypoxia profiles correlated with each other and with chronic hypoxia. However, the acute hypoxia profile showed a stronger association with local recurrence after chemoradiotherapy (p = 0.02; HR = 3.1) than the four clinical (chronic hypoxia) profiles (p = 0.2; HR = 0.9). An independent set of 174 patients confirmed that acute hypoxia is a stronger prognostic factor than chronic hypoxia for overall survival, progression-free survival, local and locoregional control. Multivariable analyses accounting for known prognostic factors substantiate this finding (p = 0.045; p = 0.042; p = 0.018 and p = 0.003, respectively). In conclusion, the four clinical hypoxia profiles are related to chronic hypoxia and not acute hypoxia. The acute hypoxia profile shows a stronger association with patient outcome and should be incorporated into existing prediction models. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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13 pages, 4150 KiB

Open AccessArticle

p53-Dependent Apoptotic Effect of Puromycin via Binding of Ribosomal Protein L5 and L11 to MDM2 and Its Combination Effect with RITA or Doxorubicin

by Ji Hoon Jung, Hyemin Lee, Ju-Ha Kim, Deok Yong Sim, Hyojin Ahn, Bonglee Kim, Suhwan Chang and Sung-Hoon Kim

Cancers 2019, 11(4), 582; https://doi.org/10.3390/cancers11040582 - 24 Apr 2019

Cited by 25 | Viewed by 6739

Abstract

Among ribosomal proteins essential for protein synthesis, the functions of ribosomal protein L5 (RPL5) and RPL11 still remain unclear to date. Here, the roles of RPL5 and RPL11 were investigated in association with p53/p21 signaling in the antitumor effect of puromycin mainly in [...] Read more.

Among ribosomal proteins essential for protein synthesis, the functions of ribosomal protein L5 (RPL5) and RPL11 still remain unclear to date. Here, the roles of RPL5 and RPL11 were investigated in association with p53/p21 signaling in the antitumor effect of puromycin mainly in HCT116 and H1299 cancer cells. Cell proliferation assays using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays and colony formation assays, cell cycle analysis, Reverse transcription polymerase chain reaction (RT-PCR) and Western blotting were performed in cancer cells. Puromycin exerted cytotoxic and anti-proliferative effects in p53 wild-type HCT116 more than in p53 null H1299 cells. Consistently, puromycin increased sub-G1, cleaved Poly (ADP-ribose) polymerase (PARP), activated p53, p21, and Mouse double minute 2 homolog (MDM2), and attenuated expression of c-Myc in HCT116 cells. Notably, puromycin upregulated the expression of RPL5 and RPL11 to directly bind to MDM2 in HCT116 cells. Conversely, deletion of RPL5 and RPL11 blocked the activation of p53, p21, and MDM2 in HCT116 cells. Also, puromycin enhanced the antitumor effect with reactivating p53 and inducing tumor apoptosis (RITA) or doxorubicin in HCT116 cells. These findings suggest that puromycin induces p53-dependent apoptosis via upregulation of RPL5 or RPL11 for binding with MDM2, and so can be used more effectively in p53 wild-type cancers by combination with RITA or doxorubicin. Full article

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18 pages, 4596 KiB

Open AccessArticle

Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors

by Jae Hwan Lee, Hyungwon Moon, Hyounkoo Han, In Joon Lee, Doyeon Kim, Hak Jong Lee, Shin-Woo Ha, Hyuncheol Kim and Jin Wook Chung

Cancers 2019, 11(4), 581; https://doi.org/10.3390/cancers11040581 - 24 Apr 2019

Cited by 22 | Viewed by 4347

Abstract

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated [...] Read more.

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) to enhance therapeutic efficiency by sonoporation under exposure to ultrasound. ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. In the VX2 rabbit tumor model, ADMB enhanced the therapeutic efficiency under ultrasound exposure, compared to free doxorubicin. The intra-arterial administration of ADMBs sufficiently reduced tumor growth by five times, compared to the control group. Changes in the ADC values and viable tumor fraction supported the fact that the antitumor effect of ADMBs were enhanced by evidence of necrosis ratio (over 70%) and survival tumor cell fraction (20%). Liver toxicity was comparable to that of conventional therapies. In conclusion, this study shows that tumor suppression can be sufficiently maximized by combining ultrasound exposure with intra-arterial ADMB administration. Full article

(This article belongs to the Special Issue Cancer Nanomedicine)

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17 pages, 3946 KiB

Open AccessArticle

Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation

by Shin-Yi Liu, Wen-Chien Huang, Hung-I Yeh, Chun-Chuan Ko, Hui-Ru Shieh, Chung-Lieh Hung, Tung-Ying Chen and Yu-Jen Chen

Cancers 2019, 11(4), 580; https://doi.org/10.3390/cancers11040580 - 24 Apr 2019

Cited by 31 | Viewed by 5968

Abstract

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential [...] Read more.

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8⁺ T cells and NKG2D⁺ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary. Full article

(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)

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14 pages, 1194 KiB

Open AccessArticle

Histopathological Imaging–Environment Interactions in Cancer Modeling

by Yaqing Xu, Tingyan Zhong, Mengyun Wu and Shuangge Ma

Cancers 2019, 11(4), 579; https://doi.org/10.3390/cancers11040579 - 24 Apr 2019

Cited by 6 | Viewed by 3215

Abstract

Histopathological imaging has been routinely conducted in cancer diagnosis and recently used for modeling other cancer outcomes/phenotypes such as prognosis. Clinical/environmental factors have long been extensively used in cancer modeling. However, there is still a lack of study exploring possible interactions of histopathological [...] Read more.

Histopathological imaging has been routinely conducted in cancer diagnosis and recently used for modeling other cancer outcomes/phenotypes such as prognosis. Clinical/environmental factors have long been extensively used in cancer modeling. However, there is still a lack of study exploring possible interactions of histopathological imaging features and clinical/environmental risk factors in cancer modeling. In this article, we explore such a possibility and conduct both marginal and joint interaction analysis. Novel statistical methods, which are “borrowed” from gene–environment interaction analysis, are employed. Analysis of The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) data is conducted. More specifically, we examine a biomarker of lung function as well as overall survival. Possible interaction effects are identified. Overall, this study can suggest an alternative way of cancer modeling that innovatively combines histopathological imaging and clinical/environmental data. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Cancers)

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9 pages, 532 KiB

Open AccessArticle

Oxaliplatin-Based Chemotherapy in Patients with Metastatic Colorectal Cancer Aged at Least 75 Years: A Post-Hoc Subgroup Analysis of Three Phase II Trials

by Gerardo Rosati, Stefano Cordio, Giorgio Reggiardo, Giuseppe Aprile, Alfredo Butera, Antonio Avallone, Aniello Tucci, Giuseppe Novello, Giuseppina Blanco, Giuseppe Caputo, Domenico Bilancia and Roberto Bordonaro

Cancers 2019, 11(4), 578; https://doi.org/10.3390/cancers11040578 - 24 Apr 2019

Cited by 4 | Viewed by 3230

Abstract

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged [...] Read more.

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged at least 75 years was included in this study. Oxaliplatin was combined with capecitabine in two trials and with uracil-tegafur (UFT) plus folinic acid in the third trial. In one study, bevacizumab was also added to chemotherapy. The median age of patients was 77 years, and all had a good performance status (0 to 1). The observed overall response rate was 45%, comparable to younger patients (51%, p = 0.49). The estimated median progression-free survival (PFS) time and overall survival (OS) time were 8.7 and 19.3 months, respectively. These results did not significantly differ from those in younger patients (8.0 months for PFS (p = 0.58) and 19.7 months for OS (p = 0.94), respectively). The most common grade 3–4 adverse events included diarrhea (13%), fatigue (13%), peripheral neuropathy (10%), and neutropenia (7%). Moreover, the toxicity was never statistically different from that in younger patients. The efficacy of oxaliplatin-based combination was maintained in fit elderly patients ≥75 years. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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17 pages, 28508 KiB

Open AccessArticle

Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts

by Holly A. Maulhardt, Lauren Hylle, Michael V. Frost, Ashley Tornio, Sara Dafoe, Leanne Drummond, David I. Quinn, Ashish M. Kamat and Gere S. diZerega

Cancers 2019, 11(4), 577; https://doi.org/10.3390/cancers11040577 - 24 Apr 2019

Cited by 14 | Viewed by 3964

Abstract

Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce^®, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce^®, IV-docetaxel and IT-vehicle were administered to [...] Read more.

Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce^®, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce^®, IV-docetaxel and IT-vehicle were administered to clear cell renal carcinoma (786-O: rats), transitional cell bladder carcinoma (UM-UC-3: mice) and prostate carcinoma (PC-3: mice). Treatments were given every 7 days with 1, 2, or 3 doses administered. Animals were followed for tumor growth and clinical signs. At necropsy, 786-O and UM-UC-3 tumor-site tissues were evaluated by H&E and IHC and analyzed by LC-MS/MS for docetaxel concentration. Two and 3 cycles of IT-NanoDoce^® significantly reduced UM-UC-3 tumor volume (p < 0.01) and eliminated most UM-UC-3 and 786-O tumors. In both models, NanoDoce^® treatment was associated with (peri)tumor-infiltrating immune cells. Lymphoid structures were observed in IT-NanoDoce^®-treated UM-UC-3 animals adjacent to tumor sites. IT-vehicle and IV-docetaxel exhibited limited immune-cell infiltration. In both studies, high levels of docetaxel were detected in NanoDoce^®-treated animals up to 50 days post-treatment. In the PC-3 study, IT-NanoDoce^® and IV-docetaxel resulted in similar tumor reduction. NanoDoce^® significantly reduced tumor volume compared to IT-vehicle in all xenografts (p < 0.0001). We hypothesize that local, persistent, therapeutic levels of docetaxel from IT-NanoDoce^® reduces tumor burden while increasing immune-cell infiltration. IT NanoDoce^® treatment of prostate, renal and bladder cancer may result in enhanced tumoricidal effects. Full article

(This article belongs to the Special Issue Locoregional Treatment and Gene Targeted Therapies for Cancer Metastasis)

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21 pages, 3522 KiB

Open AccessArticle

Deciphering the Elevated Lipid via CD36 in Mantle Cell Lymphoma with Bortezomib Resistance Using Synchrotron-Based Fourier Transform Infrared Spectroscopy of Single Cells

by Sudjit Luanpitpong, Montira Janan, Kanjana Thumanu, Jirarat Poohadsuan, Napachai Rodboon, Phatchanat Klaihmon and Surapol Issaragrisil

Cancers 2019, 11(4), 576; https://doi.org/10.3390/cancers11040576 - 24 Apr 2019

Cited by 29 | Viewed by 4509

Abstract

Despite overall progress in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. More than half of patients did not attain response to bortezomib (BTZ), the approved treatment for relapsed [...] Read more.

Despite overall progress in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. More than half of patients did not attain response to bortezomib (BTZ), the approved treatment for relapsed or refractory MCL. Understanding how MCL cells acquire BTZ resistance at the molecular level may be a key to the long-term management of MCL patients and new therapeutic strategies. We established a series of de novo BTZ-resistant human MCL-derived cells with approximately 15- to 60-fold less sensitivity than those of parental cells. Using gene expression profiling, we discovered that putative cancer-related genes involved in drug resistance and cell survival tested were mostly downregulated, likely due to global DNA hypermethylation. Significant information on dysregulated lipid metabolism was obtained from synchrotron-based Fourier transform infrared (FTIR) spectroscopy of single cells. We demonstrated for the first time an upregulation of CD36 in highly BTZ-resistant cells in accordance with an increase in their lipid accumulation. Ectopic expression of CD36 causes an increase in lipid droplets and renders BTZ resistance to various human MCL cells. By contrast, inhibition of CD36 by neutralizing antibody strongly enhances BTZ sensitivity, particularly in CD36-overexpressing cells and de novo BTZ-resistant cells. Together, our findings highlight the potential application of CD36 inhibition for BTZ sensitization and suggest the use of FTIR spectroscopy as a promising technique in cancer research. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

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16 pages, 8643 KiB

Open AccessArticle

HNRNPL Restrains miR-155 Targeting of BUB1 to Stabilize Aberrant Karyotypes of Transformed Cells in Chronic Lymphocytic Leukemia

by Sara Pagotto, Angelo Veronese, Alessandra Soranno, Veronica Balatti, Alice Ramassone, Paolo E. Guanciali-Franchi, Giandomenico Palka, Idanna Innocenti, Francesco Autore, Laura Z. Rassenti, Thomas J. Kipps, Renato Mariani-Costantini, Luca Laurenti, Carlo M. Croce and Rosa Visone

Cancers 2019, 11(4), 575; https://doi.org/10.3390/cancers11040575 - 23 Apr 2019

Cited by 11 | Viewed by 4069

Abstract

Aneuploidy and overexpression of hsa-miR-155-5p (miR-155) characterize most solid and hematological malignancies. We recently demonstrated that miR-155 sustains aneuploidy at early stages of in vitro cellular transformation. During in vitro transformation of normal human fibroblast, upregulation of miR-155 downregulates spindle checkpoint [...] Read more.

Aneuploidy and overexpression of hsa-miR-155-5p (miR-155) characterize most solid and hematological malignancies. We recently demonstrated that miR-155 sustains aneuploidy at early stages of in vitro cellular transformation. During in vitro transformation of normal human fibroblast, upregulation of miR-155 downregulates spindle checkpoint proteins as the mitotic checkpoint serine/threonine kinase budding uninhibited by benzimidazoles 1 (BUB1), the centromere protein F (CENPF) and the zw10 kinetochore protein (ZW10), compromising the chromosome alignment at the metaphase plate and leading to aneuploidy in daughter cells. Here we show that the heterogeneous nuclear ribonucleoprotein L (HNRNPL) binds to the polymorphic marker D2S1888 at the 3′UTR of BUB1 gene, impairs the miR-155 targeting, and restores BUB1 expression in chronic lymphocytic leukemia. This mechanism occurs at advanced passages of cell transformation and allows the expansion of more favorable clones. Our findings have revealed, at least in part, the molecular mechanisms behind the chromosomal stabilization of cell lines and the concept that, to survive, tumor cells cannot continuously change their genetic heritage but need to stabilize the most suitable karyotype. Full article

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15 pages, 3826 KiB

Open AccessArticle

Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer

by Jin-Sun Ryu, Sung Hoon Sim, In Hae Park, Eun Gyeong Lee, Eun Sook Lee, Yun-Hee Kim, Youngmee Kwon, Sun-Young Kong and Keun Seok Lee

Cancers 2019, 11(4), 574; https://doi.org/10.3390/cancers11040574 - 23 Apr 2019

Cited by 7 | Viewed by 5258

Abstract

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers [...] Read more.

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers were identified by gene expression analysis of PDX samples using Nanostring nCount cancer panels. Validation of predictive biomarkers for treatment response was conducted in established PDX models by in vivo drug testing. Twenty breast cancer PDX models were generated from different molecular subtypes (overall success rate, 17.5%; 3.6% for HR⁺/HER2⁻, 21.4% for HR⁺/HER2⁺, 21.9% for HR⁻/HER2⁺ and 22.5% for triple-negative breast cancer (TNBC)). The histopathologic features of original tumors were retained in the PDX models. We detected upregulated HIF1A, RAF1, AKT2 and VEGFA in TNBC cases and demonstrated the efficacy of combined treatment with sorafenib and everolimus or docetaxel and bevacizumab in each TNBC model. Additionally, we identified upregulated HIF1A in two cases of trastuzumab-exposed HR⁻/HER2⁺ PDX models and validated the efficacy of the HIF1A inhibitor, PX-478, alone or in combination with neratinib. Our results demonstrate that PDX models can be used as effective tools for predicting therapeutic markers and evaluating personalized treatment strategies in breast cancer patients with resistance to standard chemotherapy regimens. Full article

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12 pages, 1206 KiB

Open AccessReview

Dysregulation of Natural Killer Cells in Obesity

by Donal O’Shea and Andrew E. Hogan

Cancers 2019, 11(4), 573; https://doi.org/10.3390/cancers11040573 - 23 Apr 2019

Cited by 79 | Viewed by 10861

Abstract

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, [...] Read more.

Natural killer (NK) cells are a population of lymphocytes which classically form part of the innate immune system. They are defined as innate lymphocytes, due to their ability to kill infected or transformed cells without prior activation. In addition to their cytotoxic abilities, NK cells are also rapid producers of inflammatory cytokines such as interferon gamma (IFN-γ) and are therefore a critical component of early immune responses. Due to these unique abilities, NK cells are a very important component of host protection, especially anti-tumour and anti-viral immunity. Obesity is a worldwide epidemic, with over 600 million adults and 124 million children now classified as obese. It is well established that individuals who are obese are at a higher risk of many acute and chronic conditions, including cancer and viral infections. Over the past 10 years, many studies have investigated the impact of obesity on NK cell biology, detailing systemic dysregulation of NK cell functions. More recently, several studies have investigated the role of NK cells in the homeostasis of adipose tissue and the pathophysiology of obesity. In this review, we will discuss in detail these studies and focus on emerging data detailing the metabolic mechanisms altering NK cells in obesity. Full article

(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)

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19 pages, 7450 KiB

Open AccessArticle

Dysregulation of Gap Junction Function and Cytokine Production in Response to Non-Genotoxic Polycyclic Aromatic Hydrocarbons in an In Vitro Lung Cell Model

by Deedee Romo, Kalpana Velmurugan, Brad L. Upham, Lori D. Dwyer-Nield and Alison K. Bauer

Cancers 2019, 11(4), 572; https://doi.org/10.3390/cancers11040572 - 23 Apr 2019

Cited by 17 | Viewed by 3656

Abstract

Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs), prevalent contaminants in our environment, in many occupations, and in first and second-hand smoke, pose significant adverse health effects. Most research focused on the genotoxic high molecular weight PAHs (e.g., benzo[a]pyrene), however, the nongenotoxic low molecular weight (LMW) PAHs are emerging as potential co-carcinogens and tumor promoters known to dysregulate gap junctional intercellular communication (GJIC), activate mitogen activated protein kinase pathways, and induce the release of inflammatory mediators. We hypothesize that inflammatory mediators resulting from LMW PAH exposure in mouse lung epithelial cell lines are involved in the dysregulation of GJIC. We used mouse lung epithelial cell lines and an alveolar macrophage cell line in the presence of a binary PAH mixture (1:1 ratio of fluoranthene and 1-methylanthracene; PAH mixture). Parthenolide, a pan-inflammation inhibitor, reversed the PAH-induced inhibition of GJIC, the decreased CX43 expression, and the induction of KC and TNF. To further determine the direct role of a cytokine in regulating GJIC, recombinant TNF (rTNF) was used to inhibit GJIC and this response was further enhanced in the presence of the PAH mixture. Collectively, these findings support a role for inflammation in regulating GJIC and the potential to target these early stage cancer pathways for therapeutics. Full article

(This article belongs to the Special Issue Gap Junctions and Connexins in Cancer Formation, Progression, and Therapy)

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20 pages, 3344 KiB

Open AccessArticle

Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles

by Joshua R. Huot, Alyson L. Essex, Maya Gutierrez, Rafael Barreto, Meijing Wang, David L. Waning, Lilian I. Plotkin and Andrea Bonetto

Cancers 2019, 11(4), 571; https://doi.org/10.3390/cancers11040571 - 23 Apr 2019

Cited by 26 | Viewed by 4960

Abstract

Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid [...] Read more.

Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid tumors, are frequently accompanied by several side effects, including loss of muscle mass and strength. In the present study we aimed to investigate the molecular mechanisms associated with the occurrence of muscle toxicities in in vivo conditions. Hence, we treated 8-week old healthy CD2F1 male mice with MKIs for up to six weeks and observed decreased skeletal and cardiac muscle mass, consistent with muscle weakness. Modulation of ERK1/2 and GSK3β, as well as increased expression of markers of autophagy, previously associated with muscle atrophy conditions, were shown in skeletal muscle upon treatment with either drug. MKIs also promoted cardiac abnormalities consistent with reduced left ventricular mass, internal diameter, posterior wall thickness and stroke volume, despite unchanged overall function. Notably, different signaling pathways were affected in the heart, including reduced expression of mitochondrial proteins, and elevated AKT, GSK3β, mTOR, MEK1/2 and ERK1/2 phosphorylation. Combined, our data demonstrate detrimental effects on skeletal and cardiac muscle in association with chronic administration of MKIs, although different mechanisms would seem to contribute to the cachectic phenotype in the two tissues. Full article

(This article belongs to the Special Issue Cancer Cachexia)

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16 pages, 712 KiB

Open AccessArticle

Prognostic Value of Genetic Alterations in Elderly Patients with Acute Myeloid Leukemia: A Single Institution Experience

by Maël Heiblig, Hélène Labussière-Wallet, Franck Emmanuel Nicolini, Mauricette Michallet, Sandrine Hayette, Pierre Sujobert, Adriana Plesa, Marie Balsat, Etienne Paubelle, Fiorenza Barraco, Isabelle Tigaud, Sophie Ducastelle, Eric Wattel, Gilles Salles and Xavier Thomas

Cancers 2019, 11(4), 570; https://doi.org/10.3390/cancers11040570 - 22 Apr 2019

Cited by 13 | Viewed by 3520

Abstract

Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity [...] Read more.

Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity in patients aged 60 years or older. On the 495 patients of our cohort, DNMT3A R882 (25.2%), NPM1 (23.7%) and FLT3-ITD (16.8%) were the most frequent molecular mutations found at diagnosis. In this elderly population, intensive chemotherapy seemed to be a suitable option in terms of early death and survival, except for normal karyotype (NK) NPM1−FLT3-ITD+ patients and those aged over 70 within the adverse cytogenetic/molecular risk group. The FLT3-ITD mutation was systematically associated with an unfavorable outcome, independently of the ratio. NK NPM1+/FLT3-TKD+ genotype tends to confer a good prognosis in patients treated intensively. Regarding minimal residual disease prognostic value, overall survival was significantly better for patients achieving a 4 log NPM1 reduction (median OS: 24.4 vs. 12.8 months, p = 0.013) but did not reach statistical significance for progression free survival. This retrospective study highlights that intensive chemotherapy may not be the most appropriate option for each elderly patient and that molecular markers may help treatment intensity decision-making. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia)

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12 pages, 978 KiB

Open AccessReview

The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma

by Sascha Marx, Yong Xiao, Marcel Baschin, Maximilian Splittstöhser, Robert Altmann, Eileen Moritz, Gabriele Jedlitschky, Sandra Bien-Möller, Henry W.S. Schroeder and Bernhard H. Rauch

Cancers 2019, 11(4), 569; https://doi.org/10.3390/cancers11040569 - 22 Apr 2019

Cited by 24 | Viewed by 5287

Abstract

The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant [...] Read more.

The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant diseases during the last decade. Malignant gliomas differ tremendously from malignancies outside the central nervous system because they virtually never form distant metastases. This review summarizes the current understanding of the platelet–immune cell communication and its potential role in glioma resistance and progression. Particularly, we focus on platelet-derived proinflammatory modulators, such as sphingosine-1-phosphate (S1P). The multifaceted interaction with immune cells puts the platelet into an interesting perspective regarding the recent advances in immunotherapeutic approaches in malignant glioma. Full article

(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)

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21 pages, 3844 KiB

Open AccessArticle

MSC.sTRAIL Has Better Efficacy than MSC.FL-TRAIL and in Combination with AKTi Blocks Pro-Metastatic Cytokine Production in Prostate Cancer Cells

by Andrea Mohr, Tianyuan Chu, Greg N. Brooke and Ralf M. Zwacka

Cancers 2019, 11(4), 568; https://doi.org/10.3390/cancers11040568 - 21 Apr 2019

Cited by 21 | Viewed by 5650

Abstract

Cell therapy is a promising new treatment option for cancer. In particular, mesenchymal stem cells (MSCs) have shown potential in delivering therapeutic genes in various tumour models and are now on the verge of being tested in the clinic. A number of therapeutic [...] Read more.

Cell therapy is a promising new treatment option for cancer. In particular, mesenchymal stem cells (MSCs) have shown potential in delivering therapeutic genes in various tumour models and are now on the verge of being tested in the clinic. A number of therapeutic genes have been examined in this context, including the death ligand TRAIL. For cell therapy, it can be used in its natural form as a full-length and membrane-bound protein (FL-TRAIL) or as an engineered version commonly referred to as soluble TRAIL (sTRAIL). As to which is more therapeutically efficacious, contradicting results have been reported. We discovered that MSCs producing sTRAIL have significantly higher apoptosis-inducing activity than cells expressing FL-TRAIL and found that FL-TRAIL, in contrast to sTRAIL, is not secreted. We also demonstrated that TRAIL does induce the expression of pro-metastatic cytokines in prostate cancer cells, but that this effect could be overcome through combination with an AKT inhibitor. Thus, a combination consisting of small-molecule drugs specifically targeting tumour cells in combination with MSC.sTRAIL, not only provides a way of sensitising cancer cells to TRAIL, but also reduces the issue of side-effect-causing cytokine production. This therapeutic strategy therefore represents a novel targeted treatment option for advanced prostate cancer and other difficult to treat tumours. Full article

(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)

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18 pages, 1048 KiB

Open AccessArticle

Immunophenotype of T Cells Expressing Programmed Death-1 and Cytotoxic T Cell Antigen-4 in Early Lung Cancer: Local vs. Systemic Immune Response

by Iwona Kwiecien, Tomasz Skirecki, Małgorzata Polubiec-Kownacka, Agata Raniszewska and Joanna Domagala-Kulawik

Cancers 2019, 11(4), 567; https://doi.org/10.3390/cancers11040567 - 21 Apr 2019

Cited by 19 | Viewed by 4203

Abstract

The overexpression of programmed death-1 (PD-1) and cytotoxic T cell antigen 4 (CTLA-4) receptors on T cells are among the major mechanisms of tumor immunoevasion. However, the expression pattern of these receptors on T cell subpopulations of a different activation status and at [...] Read more.

The overexpression of programmed death-1 (PD-1) and cytotoxic T cell antigen 4 (CTLA-4) receptors on T cells are among the major mechanisms of tumor immunoevasion. However, the expression pattern of these receptors on T cell subpopulations of a different activation status and at different sites is poorly characterized. Thus, we analyzed the expression of PD-1 and CTLA-4 on the naïve, activated, memory, and activated memory T cells. Bronchoalveolar lavage fluid (BALF) from the lung affected by lung cancer (clBALF), the opposite ‘healthy’ lung (hlBALF), and peripheral blood (PB) samples were collected from 32 patients. The cells were analyzed by multiparameter flow cytometry. The proportion of memory, activated, and activated memory CD8+ cells with the expression of PD-1 and CTLA-4 were elevated in the clBALF when compared to the hlBALF (insignificantly), but these proportions were significantly higher in the BALF when compared with the PB. The proportions of PD-1+ and CTLA-4+ T cells were elevated in the squamous cell carcinoma when compared to the adenocarcinoma patients. Also, the expression of PD-1 and CTLA-4 on T cells from the BALF was significantly higher than from PB. We report for the first time the differential expression of checkpoint molecules on CD4+ and CD8+ lymphocytes at a different stage of activation in the local environment of lung cancer. Moreover, the circulating T cells have a distinct expression of these receptors, which suggests their poor utility as biomarkers for immunotherapy. Full article

(This article belongs to the Special Issue Signaling Pathways and Immune Checkpoint Regulation in Cancer)

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14 pages, 4375 KiB

Open AccessArticle

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

by Jasmina Makarević, Jochen Rutz, Eva Juengel, Sebastian Maxeiner, Igor Tsaur, Felix K.-H. Chun, Jürgen Bereiter-Hahn and Roman A. Blaheta

Cancers 2019, 11(4), 566; https://doi.org/10.3390/cancers11040566 - 19 Apr 2019

Cited by 16 | Viewed by 4059

Abstract

The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), [...] Read more.

The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens. Full article

(This article belongs to the Collection Histone Modification in Cancer)

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8 pages, 227 KiB

Open AccessFeature PaperPerspective

The Patient with Difficult Cancer Pain

by Sebastiano Mercadante

Cancers 2019, 11(4), 565; https://doi.org/10.3390/cancers11040565 - 19 Apr 2019

Cited by 20 | Viewed by 4320

Abstract

Most patients with cancer pain can be managed with relatively simple methods using oral analgesics at relatively low doses, even for prolonged periods of time. However, in some clinical conditions pain may be more difficult to manage. Various factors can interfere with a [...] Read more.

Most patients with cancer pain can be managed with relatively simple methods using oral analgesics at relatively low doses, even for prolonged periods of time. However, in some clinical conditions pain may be more difficult to manage. Various factors can interfere with a desirable and favorable analgesic response. Data from several studies assessing factors of negative pain prognosis have indicated that neuropathic pain, incident pain, psychological distress, opioid addiction, and baseline pain intensity were associated with more difficult pain control. In this narrative review, the main factors that make the therapeutic response to opioids difficult are examined. Full article

(This article belongs to the Special Issue Cancer Pains)

20 pages, 1254 KiB

Open AccessEditor’s ChoiceReview

Tumor-Associated Neutrophils in Cancer: Going Pro

by Lingyun Wu, Sugandha Saxena, Mohammad Awaji and Rakesh K. Singh

Cancers 2019, 11(4), 564; https://doi.org/10.3390/cancers11040564 - 19 Apr 2019

Cited by 248 | Viewed by 12595

Abstract

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in [...] Read more.

The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies. Full article

(This article belongs to the Special Issue Targeting Innate Immunity Cells in Cancer)

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16 pages, 674 KiB

Open AccessReview

Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

by Elisa Bergaggio and Roberto Piva

Cancers 2019, 11(4), 563; https://doi.org/10.3390/cancers11040563 - 19 Apr 2019

Cited by 40 | Viewed by 7528

Abstract

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO₂. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we [...] Read more.

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO₂. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we summarized findings addressing the impact of IDH mutants in rare pathologies and focused on the relevance of non-mutated IDH enzymes in tumors. Several pieces of evidence suggest that the enzymatic inhibition of IDHs may have therapeutic potentials also in wild-type IDH cancers. Moreover, IDHs inhibition could enhance the efficacy of canonical cancer therapies, such as chemotherapy, target therapy, and radiotherapy. However, further studies are required to elucidate whether IDH proteins are diagnostic/prognostic markers, instrumental for tumor initiation and maintenance, and could be exploited as targets for anticancer therapy. The development of wild-type IDH inhibitors is expected to improve our understanding of a potential non-oncogenic addition to IDH1/2 activities and to fully address their applicability in combination with other therapies. Full article

(This article belongs to the Special Issue Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities)

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18 pages, 2374 KiB

Open AccessArticle

Dual Targeting of Y-Box Binding Protein-1 and Akt Inhibits Proliferation and Enhances the Chemosensitivity of Colorectal Cancer Cells

by Eva Maier, Felix Attenberger, Aadhya Tiwari, Konstanze Lettau, Simone Rebholz, Birgit Fehrenbacher, Martin Schaller, Cihan Gani and Mahmoud Toulany

Cancers 2019, 11(4), 562; https://doi.org/10.3390/cancers11040562 - 19 Apr 2019

Cited by 19 | Viewed by 4618

Abstract

KRAS-mutated colorectal cancers (CRCs) are resistant to cetuximab treatment. The multifunctional Y-box binding protein 1 (YB-1) is overexpressed in CRC and is associated with chemoresistance. In this study, the effects of oncogenic mutated KRAS(G12V) and KRAS(G13D) on YB-1 phosphorylation were investigated in CRC [...] Read more.

KRAS-mutated colorectal cancers (CRCs) are resistant to cetuximab treatment. The multifunctional Y-box binding protein 1 (YB-1) is overexpressed in CRC and is associated with chemoresistance. In this study, the effects of oncogenic mutated KRAS(G12V) and KRAS(G13D) on YB-1 phosphorylation were investigated in CRC cells. The effects of the inhibition of p90 ribosomal S6 kinase (RSK) on YB-1 phosphorylation, cell proliferation and survival were tested with and without treatment with 5-fluorouracil using pharmacological inhibitors and siRNA. YB-1 phosphorylation status and subcellular distribution in CRC patient tissues were determined by immunofluorescence staining and confocal microscopy. Endogenous expression of mutated KRAS(G13D) and conditional expression of KRAS(G12V) significantly stimulated YB-1 phosphorylation via RSK and were associated with cetuximab resistance. Inhibition of YB-1 by targeting RSK stimulated the Akt signaling pathway, and this stimulation occurred independently of KRAS mutational status. Akt activation interfered with the antiproliferative effect of the RSK inhibitor. Consequently, dual targeting of RSK and Akt efficiently inhibited cell proliferation in KRAS(G13D)-mutated HCT116 and KRAS wild-type SW48 cells. Treatment with 5-fluorouracil (5-FU) significantly enhanced YB-1 phosphorylation in KRAS(G13D)-mutated HCT116 cells but not in KRAS wild-type SW48 cells. Dual targeting of Akt and RSK sensitized HCT116 cells to 5-FU by stimulating 5-FU-induced apoptosis and inhibiting repair of 5-FU-induced DNA damage. YB-1 was highly phosphorylated in CRC patient tumor tissues and was mainly localized in the nucleus. Together, dual targeting of RSK and Akt may be an alternative molecular targeting approach to cetuximab for treating CRC in which YB-1 is highly phosphorylated. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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15 pages, 4008 KiB

Open AccessArticle

Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer

by Sajida Ibrahim, Hassan Dakik, Christophe Vandier, Romain Chautard, Gilles Paintaud, Frédéric Mazurier, Thierry Lecomte, Maxime Guéguinou and William Raoul

Cancers 2019, 11(4), 561; https://doi.org/10.3390/cancers11040561 - 19 Apr 2019

Cited by 55 | Viewed by 6137

Abstract

Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca²⁺-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca²⁺ channels and Ca²⁺-dependent potassium channels [...] Read more.

Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca²⁺-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca²⁺ channels and Ca²⁺-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca²⁺ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca²⁺ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca²⁺ channels remodeling in CRC. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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17 pages, 2798 KiB

Open AccessArticle

Orthotopic Patient-Derived Xenografts of Gastric Cancer to Decipher Drugs Effects on Cancer Stem Cells and Metastatic Dissemination

by Julie Giraud, Damien Bouriez, Lornella Seeneevassen, Benoit Rousseau, Elodie Sifré, Alban Giese, Francis Mégraud, Philippe Lehours, Pierre Dubus, Caroline Gronnier and Christine Varon

Cancers 2019, 11(4), 560; https://doi.org/10.3390/cancers11040560 - 19 Apr 2019

Cited by 11 | Viewed by 5876

Abstract

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process [...] Read more.

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)

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21 pages, 376 KiB

Open AccessReview

New Insights into the Implication of Epigenetic Alterations in the EMT of Triple Negative Breast Cancer

by Noura Khaled and Yannick Bidet

Cancers 2019, 11(4), 559; https://doi.org/10.3390/cancers11040559 - 18 Apr 2019

Cited by 71 | Viewed by 8223

Abstract

Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. During the last two decades, the use of targeted therapies has emerged in clinical research in order [...] Read more.

Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. During the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. However, the triple negative breast cancer (TNBC) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. This aggressive breast cancer entity lacks expression of oestrogen receptor (ER) and progesterone receptor (PR), and it does not overexpress human epidermal growth factor receptor 2 (HER2). The major reason for TNBC poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. Metastases occur after an epithelial-mesenchymal transition EMT of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. Cancer-associated EMT consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. Recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. This review builds a picture of the epigenetic modifications implicated in the EMT of breast cancer. It focuses on TNBC and allows comparisons with other subtypes. It emphasizes the role of the main epigenetic modifications lncRNAs, miRNAs, histone and DNA- modifications in tumour invasion and appearance of metastases. These epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for TNBC. Full article

16 pages, 5726 KiB

Open AccessArticle

TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway

by Yan Wang, Yan-Xiang Qi, Zenghua Qi and Suk-Ying Tsang

Cancers 2019, 11(4), 558; https://doi.org/10.3390/cancers11040558 - 18 Apr 2019

Cited by 42 | Viewed by 6439

Abstract

Currently, there is no effective molecular-based therapy for triple-negative breast cancer (TNBC). Canonical transient receptor potential isoform 3 (TRPC3) was previously shown to be upregulated in breast cancer biopsy tissues when compared to normal breast tissues. However, the biological role of TRPC3 in [...] Read more.

Currently, there is no effective molecular-based therapy for triple-negative breast cancer (TNBC). Canonical transient receptor potential isoform 3 (TRPC3) was previously shown to be upregulated in breast cancer biopsy tissues when compared to normal breast tissues. However, the biological role of TRPC3 in breast cancer still remains to be elucidated. In this study, subcellular fractionation followed by Western blot and immunocytochemistry showed that TRPC3 was over-expressed on the plasma membrane of TNBC line MDA-MB-231 when compared to an estrogen receptor-positive cell line MCF-7. TRPC3 blocker Pyr3 and dominant negative of TRPC3 attenuated proliferation, induced apoptosis and sensitized cell death to chemotherapeutic agents in MDA-MB-231 as measured by proliferation assays. Interestingly, Ras GTPase-activating protein 4 (RASA4), a Ca²⁺-promoted Ras-MAPK pathway suppressor, was found to be located on the plasma membrane of MDA-MB-231. Blocking TRPC3 decreased the amount of RASA4 located on the plasma membrane, with concomitant activation of MAPK pathways. Our results suggest that, in TNBC MDA-MB-231 cells, Ca²⁺ influx through TRPC3 channel sustains the presence of RASA4 on the plasma membrane where it inhibits the Ras-MAPK pathway, leading to proliferation and apoptosis resistance. Our study reveals the novel TRPC3-RASA4-MAPK signaling cascade in TNBC cells and suggests that TRPC3 may be exploited as a potential therapeutic target for TNBC. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

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