Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 1999;284:808-12. [PMID: 10221914 DOI: 10.1126/science.284.5415.808] [Citation(s) in RCA: 782] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]

For:	Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D. Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. Science 1999;284:808-12. [PMID: 10221914 DOI: 10.1126/science.284.5415.808] [Citation(s) in RCA: 782] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]

Number

Cited by Other Article(s)

Chitoran E, Rotaru V, Stefan DC, Gullo G, Simion L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab-20 Years of Therapeutic Success and Controversy. Cancers (Basel) 2025;17:1126. [PMID: 40227654 PMCID: PMC11988089 DOI: 10.3390/cancers17071126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/22/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open

Abstract

The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.

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Avnet S, Mizushima E, Severino B, Lipreri MV, Scognamiglio A, Corvino A, Baldini N, Cortini M. Antagonizing the S1P-S1P3 Axis as a Promising Anti-Angiogenic Strategy. Metabolites 2025;15:178. [PMID: 40137142 PMCID: PMC11944055 DOI: 10.3390/metabo15030178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 02/25/2025] [Accepted: 03/03/2025] [Indexed: 03/27/2025] Open

Abstract

BACKGROUND

Angiogenesis, the process of new blood vessel formation, is critically regulated by a balance of pro- and anti-angiogenic factors. This process plays a central role in tumor progression and is modulated by tumor cells. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule acting via G-protein-coupled receptors (S1PR1-5), has emerged as a key mediator of vascular development and pathological angiogenesis in cancer. Consequently, targeting the S1P-S1PRs axis represents a promising strategy for antiangiogenic therapies. This study explores S1PR3 as a potential therapeutic target in osteosarcoma, the most common primary bone malignancy, which we have previously demonstrated to secrete S1P within the acidic tumor microenvironment.

METHODS

The effects of KRX-725-II and its derivatives, Tic-4-KRX-725-II and [D-Tic]4-KRX-725-II-pepducins acting as S1PR3 antagonists as allosteric modulators of GPCR activity-were tested on metastatic osteosarcoma cells (143B) for proliferation and migration inhibition. Anti-angiogenic activity was assessed using endothelial cells (HUVEC) through proliferation and tubulogenesis assays in 2D, alongside sprouting and migration analyses in a 3D passively perfused microfluidic chip.

RESULTS

S1PR3 inhibition did not alter osteosarcoma cell growth or migration. However, it impaired endothelial cell tubulogenesis up to 75% and sprouting up to 30% in respect to controls. Conventional 2D assays revealed reduced tubule nodes and length, while 3D microfluidic models demonstrated diminished sprouting area and maximum migration distance, indicating S1PR3's role in driving endothelial cell differentiation.

CONCLUSIONS

These findings highlight S1PR3 as a critical regulator of angiogenesis and posit its targeting as a novel anti-angiogenic strategy, particularly for aggressive, S1P-secreting tumors with pronounced metastatic potential and an acidic microenvironment.

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Li J, Wang D, Duan Q, Su N, Li X, Qiu H. The efficacy of anti-angiogenic drugs in gastric-type endocervical adenocarcinoma: A retrospective study. J Obstet Gynaecol Res 2025;51:e16247. [PMID: 39988602 DOI: 10.1111/jog.16247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 02/09/2025] [Indexed: 02/25/2025]

Abstract

OBJECTIVES

Gastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients.

METHODS

Patients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method.

RESULTS

A total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively).

CONCLUSION

We firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.

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Guelfi S, Hodivala-Dilke K, Bergers G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat Rev Cancer 2024;24:655-675. [PMID: 39210063 DOI: 10.1038/s41568-024-00736-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/04/2024]

Chitoran E, Rotaru V, Ionescu SO, Gelal A, Capsa CM, Bohiltea RE, Mitroiu MN, Serban D, Gullo G, Stefan DC, Simion L. Bevacizumab-Based Therapies in Malignant Tumors-Real-World Data on Effectiveness, Safety, and Cost. Cancers (Basel) 2024;16:2590. [PMID: 39061228 PMCID: PMC11274419 DOI: 10.3390/cancers16142590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/08/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open

Abstract

Overall, it is estimated that more than 3,500,000 patients have received Bevacizumab as part of systemic oncologic treatment. Bevacizumab and its biosimilars are currently marketed in over 130 countries. Given the wide usage of Bevacizumab in current oncological practice, it is very important to compare the "real-world" results to those obtained in controlled clinical trials. This study aims to describe the clinical experience of using Bevacizumab in a large cohort of cancer patients in "non-controlled real-world" conditions with regard to effectiveness, safety, and cost of therapy.

METHODS

For this purpose, we conducted an open, observational, retrospective study involving all patients treated for solid malignant tumors in the Bucharest Institute of Oncology with "Prof. Dr. Al. Trestioreanu" with Bevacizumab-based systemic therapy, between 2017 and 2021.

RESULTS

The study consisted of 657 treatment episodes in 625 patients (F/B = 1.62/1, with a median age of 57.6 years) which were treated for malignant tumors (majority colorectal, non-small cell lung, ovarian, and breast cancer). First-line treatment was administered in 229 patients, and the rest received Bevacizumab as second or subsequent lines of treatment. The overall response rate to Bevacizumab-based therapies was around 60-65% across all indication except for subsequent treatment lines in colorectal and ovarian cancers, where lower values were recorded (27.1%, and 31.5% respectively). Median PFS for the entire cohort was 8.2 months (95% CI 6.8-9.6), and the median OS was 13.2 months (95% CI 11.5-14.9). Usual bevacizumab-related toxicities were observed, including bleeding, hypertension, wound-healing complications, gastrointestinal perforation, other types of fistulas, septic complications, and thromboembolic events. Although the clinical benefits are undeniable, the addition of Bevacizumab to standard chemotherapy increased the overall treatment cost by 213%.

CONCLUSIONS

Bevacizumab remains a high-cost therapy, but it can add to clinical benefits (like overall survival, progression-free survival, and response rate) when used in conjunction with standard chemotherapy. Similar results as those presented in various controlled trials are observable even on unselected cohorts of patients in the uncontrolled conditions of "real-world" oncological practice. Off-label usage is encountered in clinical practice, and this aspect should be monitored given the potential adverse effects of the therapy.

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Affiliation(s)

Elena Chitoran Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Vlad Rotaru Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Sinziana-Octavia Ionescu Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Aisa Gelal Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Cristina-Mirela Capsa Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania Radiology Department, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
Roxana-Elena Bohiltea Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
Madalina-Nicoleta Mitroiu Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
Dragos Serban Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania Surgery Department 4, Bucharest University Emergency Hospital, 050098 Bucharest, Romania
Giuseppe Gullo Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
Daniela-Cristina Stefan Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
Laurentiu Simion Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania

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Yamashita A, Park SH, Zeng L, Stiles WR, Ahn S, Bao K, Kim J, Kang H, Choi HS. H-Dot Mediated Nanotherapeutics Mitigate Systemic Toxicity of Platinum-Based Anticancer Drugs. Int J Mol Sci 2023;24:15466. [PMID: 37895146 PMCID: PMC10607179 DOI: 10.3390/ijms242015466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/17/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open

Affiliation(s)

Atsushi Yamashita Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Seung Hun Park Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Lingxue Zeng Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.) Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
Wesley R. Stiles Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Sung Ahn Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Kai Bao Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Jonghan Kim Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.) Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
Homan Kang Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)
Hak Soo Choi Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; (A.Y.); (S.H.P.); (L.Z.); (W.R.S.); (S.A.); (K.B.); (J.K.); (H.K.)

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Egidi MJ, Krug S, Haybaeck J, Michl P, Griesmann H. Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis. Br J Cancer 2023;129:1225-1237. [PMID: 37620408 PMCID: PMC10575939 DOI: 10.1038/s41416-023-02389-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 07/12/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open

Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023;11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open

Manohar-Sindhu S, Merfeld-Clauss S, Goddard Y, March KL, Traktuev DO. Diminished vasculogenesis under inflammatory conditions is mediated by Activin A. Angiogenesis 2023;26:423-436. [PMID: 36977946 DOI: 10.1007/s10456-023-09873-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/06/2023] [Indexed: 03/30/2023]

Abstract

Severe inflammatory stress often leads to vessel rarefaction and fibrosis, resulting in limited tissue recovery. However, signaling pathways mediating these processes are not completely understood. Patients with ischemic and inflammatory conditions have increased systemic Activin A level, which frequently correlates with the severity of pathology. Yet, Activin A's contribution to disease progression, specifically to vascular homeostasis and remodeling, is not well defined. This study investigated vasculogenesis in an inflammatory environment with an emphasis on Activin A's role. Exposure of endothelial cells (EC) and perivascular cells (adipose stromal cells, ASC) to inflammatory stimuli (represented by blood mononuclear cells from healthy donors activated with lipopolysaccharide, aPBMC) dramatically decreased EC tubulogenesis or caused vessel rarefaction compared to control co-cultures, concurrent with increased Activin A secretion. Both EC and ASC upregulated Inhibin Ba mRNA and Activin A secretion in response to aPBMC or their secretome. We identified TNFα (in EC) and IL-1β (in EC and ASC) as the exclusive inflammatory factors, present in aPBMC secretome, responsible for induction of Activin A. Similar to ASC, brain and placental pericytes upregulated Activin A in response to aPBMC and IL-1β, but not TNFα. Both these cytokines individually diminished EC tubulogenesis. Blocking Activin A with neutralizing IgG mitigated detrimental effects of aPBMC or TNFα/IL-1β on tubulogenesis in vitro and vessel formation in vivo. This study delineates the signaling pathway through which inflammatory cells have a detrimental effect on vessel formation and homeostasis, and highlights the central role of Activin A in this process. Transitory interference with Activin A during early phases of inflammatory or ischemic insult, with neutralizing antibodies or scavengers, may benefit vasculature preservation and overall tissue recovery.

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Montico F, Lamas CDA, Rossetto IMU, Baseggio AM, Cagnon VHA. Lobe-specific responses of TRAMP mice dorsolateral prostate following celecoxib and nintedanib therapy. J Mol Histol 2023;54:379-403. [PMID: 37335420 DOI: 10.1007/s10735-023-10130-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]

Abstract

Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-β, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-β signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-β signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.

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Tang J, Li XW, Wu Y, Su Z, He Y, Sun XW, Cao XL, Li YH, Wang BC, Zou GR. Treating radiation‑related nasopharyngeal necrosis with endostar in patient with nasopharyngeal carcinoma: A report of two cases and a literature review. Mol Clin Oncol 2023;19:57. [PMID: 37359714 PMCID: PMC10288433 DOI: 10.3892/mco.2023.2653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open

Boswell-Patterson CA, Hétu MF, Pang SC, Herr JE, Zhou J, Jain S, Bambokian A, Johri AM. Novel theranostic approaches to neovascularized atherosclerotic plaques. Atherosclerosis 2023;374:1-10. [PMID: 37149970 DOI: 10.1016/j.atherosclerosis.2023.04.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 04/05/2023] [Accepted: 04/17/2023] [Indexed: 05/09/2023]

Abstract

As the global burden of atherosclerotic cardiovascular disease continues to rise, there is an increased demand for improved imaging techniques for earlier detection of atherosclerotic plaques and new therapeutic targets. Plaque lesions, vulnerable to rupture and thrombosis, are thought to be responsible for the majority of cardiovascular events, and are characterized by a large lipid core, a thin fibrous cap, and neovascularization. In addition to supplying the plaque core with increased inflammatory factors, these pathological neovessels are tortuous and leaky, further increasing the risk of intraplaque hemorrhage. Clinically, plaque neovascularization has been shown to be a significant and independent predictor of adverse cardiovascular outcomes. Microvessels can be detected through contrast-enhanced ultrasound (CEUS) imaging, however, clinical assessment in vivo is generally limited to qualitative measures of plaque neovascularization. There is no validated standard for quantitative assessment of the microvessel networks found in plaques. Advances in our understanding of the pathological mechanisms underlying plaque neovascularization and its significant role in the morbidity and mortality associated with atherosclerosis have made it an attractive area of research in translational medicine. Current areas of research include the development of novel therapeutic and diagnostic agents to target plaque neovascularization stabilization. With recent progress in nanotechnology, nanoparticles have been investigated for their ability to specifically target neovascularization. Contrast microbubbles have been similarly engineered to carry loads of therapeutic agents and can be visualized using CEUS. This review summarizes the pathogenesis, diagnosis, clinical significance of neovascularization, and importantly the emerging areas of theranostic tool development.

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Natale G, Bocci G. Discovery and Development of Tumor Angiogenesis Assays. Methods Mol Biol 2023;2572:1-37. [PMID: 36161404 DOI: 10.1007/978-1-0716-2703-7_1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]

McClellan K, Chen EY, Kardosh A, Lopez CD, Del Rivero J, Mallak N, Rocha FG, Koethe Y, Pommier R, Mittra E, Pegna GJ. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers (Basel) 2022;14:4769. [PMID: 36230691 PMCID: PMC9563314 DOI: 10.3390/cancers14194769] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/24/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open

Aberrant transcription factors in the cancers of the pancreas. Semin Cancer Biol 2022;86:28-45. [PMID: 36058426 DOI: 10.1016/j.semcancer.2022.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/15/2022] [Accepted: 08/29/2022] [Indexed: 11/21/2022]

de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, Devel L, Dufour A. Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology. Pharmacol Rev 2022;74:712-768. [PMID: 35738680 DOI: 10.1124/pharmrev.121.000349] [Citation(s) in RCA: 201] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open

Affiliation(s)

Luiz G N de Almeida Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Hayley Thode Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Yekta Eslambolchi Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Sameeksha Chopra Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Daniel Young Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Sean Gill Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Laurent Devel Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)
Antoine Dufour Departments of Physiology and Pharmacology and Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada (L.G.N.d.A., Y.E., S.C., D.Y., A.D.); Department of Physiology and Pharmacology, University of Western Ontario, London, Canada (S.G., H.T.); and Université Paris-Saclay, CEA, INRAE, Medicaments et Technologies pour la Santé, Gif-sur-Yvette, France (L.D.)

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Platelet-Derived PDGFB Promotes Recruitment of Cancer-Associated Fibroblasts, Deposition of Extracellular Matrix and Tgfβ Signaling in the Tumor Microenvironment. Cancers (Basel) 2022;14:cancers14081947. [PMID: 35454853 PMCID: PMC9024906 DOI: 10.3390/cancers14081947] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/08/2022] [Accepted: 04/10/2022] [Indexed: 11/16/2022] Open

Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer. Cancers (Basel) 2021;14:cancers14010194. [PMID: 35008355 PMCID: PMC8750413 DOI: 10.3390/cancers14010194] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open

Abstract

Simple Summary

The survival rates for patients with pancreatic adenocarcinoma are very low. This dismal prognosis is due in part to late detection and early development of metastases, and successful treatments for pancreatic adenocarcinoma are also lacking. One potential method of treatment is immunotherapy, which has been successfully implemented in several cancers. Despite success in other cancer types, there has been little progress in pancreatic adenocarcinoma. To understand these shortcomings, we explore the roles of macrophages and neutrophils, two prominent immune cell types in the pancreatic tumor environment. In this review, we discuss how macrophages and neutrophils lead to the harsh environment that is unique to pancreatic adenocarcinoma. We further explore how these immune cells can impact standard of care therapies and decrease their effectiveness. Macrophages and neutrophils could ultimately be targeted to improve outcomes for patients with pancreatic adenocarcinoma.

Abstract

Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.

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Structural Biology of the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021;1350:91-100. [PMID: 34888845 DOI: 10.1007/978-3-030-83282-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Abstract

Cancers can be described as "rogue organs" (Balkwill FR, Capasso M, Hagemann T, J Cell Sci 125:5591-5596, 2012) because they are composed of multiple cell types and tissues. The transformed cells can recruit and alter healthy cells from surrounding tissues for their own benefit. It is these interactions that create the tumor microenvironment (TME). The TME describes the cells, factors, and extracellular matrix proteins that make up the tumor and the area around it; the biology of the TME influences tumor progression. Changes in the TME can lead to the growth and development of the tumor, the death of the tumor, or tumor metastasis. Metastasis is the process by which cancer spreads from its initial site to a different part of the body. Metastasis occurs when cancer cells enter the circulatory system or lymphatic system after they break away from a tumor. Once the cells leave, they can travel to a different part of the body and form new tumors. Therefore, understanding the TME is critical to fully understand cancer and find a way to successfully combat it. Knowledge of the TME can better inform researchers of the ability of potential therapies to reach tumor cells. It can also give researchers potential targets to kill the tumor. Instead of directly killing the cancer cells, therapies can target an aspect of the TME which could then halt tumor development or lead to tumor death. In other cases, targeting another aspect of the TME could make it easier for another therapy to kill the cancer cells, for example, using nanoparticles with collagenases to target the collagen in the surrounding environment to expose the cancer cells to drugs (Zinger A, et al, ACS Nano 13(10):11008-11021, 2019).The TME can be split simply into cells and the structural matrix. Within these groups are fibroblasts, structural proteins, immune cells, lymphocytes, bone marrow-derived inflammatory cells, blood vessels, and signaling molecules (Spill F, et al, Curr Opin Biotechnol 40:41-48, 2016; Del Prete A, et al, Curr Opin Pharmacol 35:40-47, 2017; Arneth B, Medicina (Kaunas) 56(1), 2019). From structure to providing nutrients for growth, each of these components plays a critical role in tumor maintenance. Together these components impact cancer growth, development, and resistance to therapies (Hanahan D, Coussens LM, Cancer Cell 21:309-322, 2012). In this chapter, we will describe the TME and express the importance of the cellular and structural elements of the TME.

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Matuszewska K, Ten Kortenaar S, Pereira M, Santry LA, Petrik D, Lo KM, Bridle BW, Wootton SK, Lawler J, Petrik J. Addition of an Fc-IgG induces receptor clustering and increases the in vitro efficacy and in vivo anti-tumor properties of the thrombospondin-1 type I repeats (3TSR) in a mouse model of advanced stage ovarian cancer. Gynecol Oncol 2021;164:154-169. [PMID: 34799137 DOI: 10.1016/j.ygyno.2021.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 12/27/2022]

Abstract

OBJECTIVES

Tumor vasculature is structurally abnormal, with anatomical deformities, reduced pericyte coverage and low tissue perfusion. As a result of this vascular dysfunction, tumors are often hypoxic, which is associated with an aggressive tumor phenotype, and reduced delivery of therapeutic compounds to the tumor. We have previously shown that a peptide containing the thrombospondin-1 type I repeats (3TSR) specifically targets tumor vessels and induces vascular normalization in a mouse model of epithelial ovarian cancer (EOC). However, due to its small size, 3TSR is rapidly cleared from circulation. We now introduce a novel construct with the 3TSR peptide fused to the C-terminus of each of the two heavy chains of the Fc region of human IgG1 (Fc3TSR). We hypothesize that Fc3TSR will have greater anti-tumor activity in vitro and in vivo compared to the native compound.

METHODS

Fc3TSR was evaluated in vitro using proliferation and apoptosis assays to investigate differences in efficacy compared to native 3TSR. In light of the multivalency of Fc3TSR, we also investigate whether it induces greater clustering of its functional receptor, CD36. We also compare the compounds in vivo using an orthotopic, syngeneic mouse model of advanced stage EOC. The impact of the two compounds on changes to tumor vasculature morphology was also investigated.

RESULTS

Fc3TSR significantly decreased the viability and proliferative potential of EOC cells and endothelial cells in vitro compared to native 3TSR. High-resolution imaging followed by image correlation spectroscopy demonstrated enhanced clustering of the CD36 receptor in cells treated with Fc3TSR. This was associated with enhanced downstream signaling and greater in vitro and in vivo cellular responses. Fc3TSR induced greater vascular normalization and disease regression compared to native 3TSR in an orthotopic, syngeneic mouse model of advanced stage ovarian cancer.

CONCLUSION

The development of Fc3TSR which is greater in size, stable in circulation and enhances receptor activation compared to 3TSR, facilitates its translational potential as a therapy in the treatment of metastatic advanced stage ovarian cancer.

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Krug S, Kegel T, Gress TM, Rinke A, Apostolidis L, Jann H, König A, Hörsch D, Schrader J, Ettrich TJ, Richter M, Steighardt J, Michl P. Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial. BMC Cancer 2021;21:1206. [PMID: 34772353 PMCID: PMC8588662 DOI: 10.1186/s12885-021-08900-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 10/21/2021] [Indexed: 01/04/2023] Open

Nag JK, Malka H, Appasamy P, Sedley S, Bar-Shavit R. GPCR Partners as Cancer Driver Genes: Association with PH-Signal Proteins in a Distinctive Signaling Network. Int J Mol Sci 2021;22:8985. [PMID: 34445691 PMCID: PMC8396503 DOI: 10.3390/ijms22168985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/15/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open

Sonanini D, Griessinger CM, Schörg BF, Knopf P, Dittmann K, Röcken M, Pichler BJ, Kneilling M. Low-dose total body irradiation facilitates antitumoral Th1 immune responses. Theranostics 2021;11:7700-7714. [PMID: 34335959 PMCID: PMC8315067 DOI: 10.7150/thno.61459] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 05/16/2021] [Indexed: 12/16/2022] Open

Abstract

CD4⁺ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4⁺ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4⁺ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4⁺ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4⁺ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4⁺ T cells in the clinical setting.

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Cheng K, Liu CF, Rao GW. Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors. Curr Med Chem 2021;28:2540-2564. [PMID: 32407259 DOI: 10.2174/0929867327666200514082425] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/18/2020] [Accepted: 04/23/2020] [Indexed: 11/22/2022]

Adenocarcinoma of the Prostate: Future Directions for Translational Science. Prostate Cancer 2021. [DOI: 10.36255/exonpublications.prostatecancer.translationalscience.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] Open

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021;22:ijms22073765. [PMID: 33916438 PMCID: PMC8038573 DOI: 10.3390/ijms22073765] [Citation(s) in RCA: 217] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open

Chen X, Li Y, Yao T, Jia R. Benefits of Zebrafish Xenograft Models in Cancer Research. Front Cell Dev Biol 2021;9:616551. [PMID: 33644052 PMCID: PMC7905065 DOI: 10.3389/fcell.2021.616551] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/11/2021] [Indexed: 12/14/2022] Open

Pierini S, Mishra A, Perales-Linares R, Uribe-Herranz M, Beghi S, Giglio A, Pustylnikov S, Costabile F, Rafail S, Amici A, Facciponte JG, Koumenis C, Facciabene A. Combination of vasculature targeting, hypofractionated radiotherapy, and immune checkpoint inhibitor elicits potent antitumor immune response and blocks tumor progression. J Immunother Cancer 2021;9:jitc-2020-001636. [PMID: 33563772 PMCID: PMC7875275 DOI: 10.1136/jitc-2020-001636] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open

Abstract

Background

Tumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade.

Methods

Mice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments.

Results

We demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy.

Conclusion

Our findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.

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Affiliation(s)

Stefano Pierini Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Abhishek Mishra Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Renzo Perales-Linares Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Mireia Uribe-Herranz Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Silvia Beghi Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Andrea Giglio Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Sergei Pustylnikov Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Francesca Costabile Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Stavros Rafail Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Augusto Amici School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Marche, Italy
John G Facciponte Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Costantinos Koumenis Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Andrea Facciabene Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA .,Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA

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Notohamiprodjo S, Varasteh Z, Beer AJ, Niu G, Chen X(S, Weber W, Schwaiger M. Tumor Vasculature. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00090-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open

Wu L, Zhang XHF. Tumor-Associated Neutrophils and Macrophages-Heterogenous but Not Chaotic. Front Immunol 2020;11:553967. [PMID: 33343560 PMCID: PMC7738476 DOI: 10.3389/fimmu.2020.553967] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open

Dar KB, Bhat AH, Amin S, Anjum S, Reshi BA, Zargar MA, Masood A, Ganie SA. Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View. Curr Cancer Drug Targets 2020;19:430-448. [PMID: 30073927 DOI: 10.2174/1568009618666180803104631] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 07/17/2018] [Accepted: 07/19/2018] [Indexed: 12/31/2022]

Abstract

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

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Zhang Y, Cedervall J, Hamidi A, Herre M, Viitaniemi K, D'Amico G, Miao Z, Unnithan RVM, Vaccaro A, van Hooren L, Georganaki M, Thulin Å, Qiao Q, Andrae J, Siegbahn A, Heldin CH, Alitalo K, Betsholtz C, Dimberg A, Olsson AK. Platelet-Specific PDGFB Ablation Impairs Tumor Vessel Integrity and Promotes Metastasis. Cancer Res 2020;80:3345-3358. [PMID: 32586981 DOI: 10.1158/0008-5472.can-19-3533] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 04/24/2020] [Accepted: 06/17/2020] [Indexed: 11/16/2022]

Affiliation(s)

Yanyu Zhang Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Jessica Cedervall Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Anahita Hamidi Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Melanie Herre Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Kati Viitaniemi Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
Gabriela D'Amico Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
Zuoxiu Miao Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Ragaseema Valsala Madhavan Unnithan Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.,Department of Biotechnology, Govt. Arts College, Thiruvananthapuram, India
Alessandra Vaccaro Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
Luuk van Hooren Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
Maria Georganaki Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
Åsa Thulin Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Qi Qiao Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Johanna Andrae Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
Agneta Siegbahn Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Carl-Henrik Heldin Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden
Kari Alitalo Wihuri Research Institute and Translational Cancer Medicine Research Program, Biomedicum Helsinki, 00014 University of Helsinki, Yliopistonkatu, Helsinki, Finland
Christer Betsholtz Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.,ICMC (Integrated Cardio Metabolic Centre), Karolinska Institutet, Novum, Blickagången 6, Huddinge, Sweden
Anna Dimberg Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden
Anna-Karin Olsson Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala, Sweden.

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Saman H, Raza SS, Uddin S, Rasul K. Inducing Angiogenesis, a Key Step in Cancer Vascularization, and Treatment Approaches. Cancers (Basel) 2020;12:1172. [PMID: 32384792 PMCID: PMC7281705 DOI: 10.3390/cancers12051172] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/10/2020] [Accepted: 04/17/2020] [Indexed: 12/27/2022] Open

Kassab AE, El‐Dash Y, Gedawy EM. Novel pyrazolopyrimidine urea derivatives: Synthesis, antiproliferative activity, VEGFR‐2 inhibition, and effects on the cell cycle profile. Arch Pharm (Weinheim) 2020;353:e1900319. [DOI: 10.1002/ardp.201900319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 01/11/2023]

Park GK, Lee JH, Soriano E, Choi M, Bao K, Katagiri W, Kim DY, Paik JH, Yun SH, Frangioni JV, Clancy TE, Kashiwagi S, Henary M, Choi HS. Rapid and Selective Targeting of Heterogeneous Pancreatic Neuroendocrine Tumors. iScience 2020;23:101006. [PMID: 32268281 PMCID: PMC7139119 DOI: 10.1016/j.isci.2020.101006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 02/10/2020] [Accepted: 03/18/2020] [Indexed: 01/12/2023] Open

Affiliation(s)

G Kate Park Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Jeong Heon Lee Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Eduardo Soriano Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Ave SE, Atlanta, Georgia 30303, USA
Myunghwan Choi Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, MA 02139, USA
Kai Bao Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Wataru Katagiri Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Do-Yeon Kim Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Ji-Hye Paik Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Seok-Hyun Yun Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, MA 02139, USA
John V Frangioni Curadel, LLC, Natick, MA 01760, USA
Thomas E Clancy Division of Surgical Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215, USA
Satoshi Kashiwagi Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Maged Henary Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Ave SE, Atlanta, Georgia 30303, USA.
Hak Soo Choi Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

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Guerin MV, Finisguerra V, Van den Eynde BJ, Bercovici N, Trautmann A. Preclinical murine tumor models: a structural and functional perspective. eLife 2020;9:e50740. [PMID: 31990272 PMCID: PMC6986875 DOI: 10.7554/elife.50740] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 01/06/2020] [Indexed: 12/14/2022] Open

Michelotti FC, Bowden G, Küppers A, Joosten L, Maczewsky J, Nischwitz V, Drews G, Maurer A, Gotthardt M, Schmid AM, Pichler BJ. PET/MRI enables simultaneous in vivo quantification of β-cell mass and function. Am J Cancer Res 2020;10:398-410. [PMID: 31903128 PMCID: PMC6929626 DOI: 10.7150/thno.33410] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022] Open

Abstract

Non-invasive imaging of β-cells represents a desirable preclinical and clinical tool to monitor the change of β-cell mass and the loss of function during pre-diabetic stages. Although it is widely accepted that manganese (Mn) ions are actively gated by voltage-dependent calcium channels (VDCC) in response to glucose metabolism, little is known on its specificity in vivo for quantification of islet β-cell function using Mn and magnetic resonance imaging (MRI). On the other hand, glucagon-like-peptide-1 receptor (GLP-1R) represents a validated target for the estimation of β-cell mass using radiolabeled exendin-4 (Ex4) and positron emission tomography (PET). However, a multiparametric imaging workflow revealing β-cell mass and function quantitatively is still missing. Methods: We developed a simultaneous PET/MRI protocol to comprehensively quantify in vivo changes in β-cell mass and function by targeting, respectively, GLP-1R and VDCC coupled with insulin secretion. Differences in the spatial distribution of Mn and radiolabeled Ex4 were monitored overtime in native and transgenic pancreata, characterized by spontaneous pancreatic neuroendocrine tumor development. Follow-up with mass spectrometry imaging (MSI) and autoradiography allowed the ex vivo validation of the specificity of Mn and PET tracer uptake and the detection of endogenous biometals, such as calcium and zinc, throughout the endocrine and exocrine pancreas. Results: Our in vivo data based on a volumetric PET/MRI readout for native pancreata and insulinomas connects uptake of Mn measured at early imaging time points to high non-specific binding by the exocrine tissue, while specific retention was only found 24 h post injection. These results are supported by cross-validation of the spatial distribution of exogenous ⁵⁵Mn and endogenous ⁴⁴Ca and ⁶⁴Zn as well with the specific internalization of the radiolabeled peptide targeting GLP-1R. Conclusion: Simultaneous PET/MR imaging of the pancreas enabled the comprehensive in vivo quantification of β-cell function and mass using Mn and radiolabeled Ex4. Most important, our data revealed that only late time-point measurements reflect the Mn uptake in the islet β-cells, while early time points detect non-specific accumulation of Mn in the exocrine pancreas.

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Bochner F, Mohan V, Zinger A, Golani O, Schroeder A, Sagi I, Neeman M. Intravital imaging of vascular anomalies and extracellular matrix remodeling in orthotopic pancreatic tumors. Int J Cancer 2019;146:2209-2217. [PMID: 31661557 DOI: 10.1002/ijc.32759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/28/2019] [Accepted: 10/15/2019] [Indexed: 11/09/2022]

Saw PE, Song EW. Phage display screening of therapeutic peptide for cancer targeting and therapy. Protein Cell 2019;10:787-807. [PMID: 31140150 PMCID: PMC6834755 DOI: 10.1007/s13238-019-0639-7] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/21/2019] [Indexed: 12/14/2022] Open

Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA. Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival. Cancer Res 2019;79:6190-6203. [PMID: 31672843 DOI: 10.1158/0008-5472.can-19-1116] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 09/03/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023]

Affiliation(s)

Paul C Moore Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California
Jenny Y Qi Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California
Maike Thamsen Department of Pathology, University of California, San Francisco, San Francisco, California.,Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California.,California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California
Rajarshi Ghosh Department of Pathology, University of California, San Francisco, San Francisco, California.,Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California.,California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California
Justin Peng Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California
Micah J Gliedt Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California
Rosa Meza-Acevedo Department of Pathology, University of California, San Francisco, San Francisco, California.,Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California.,California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California
Rachel E Warren Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California
Annie Hiniker Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California
Grace E Kim Department of Pathology, University of California, San Francisco, San Francisco, California.,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
Dustin J Maly Department of Chemistry, University of Washington, Seattle, Washington
Bradley J Backes Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California
Feroz R Papa Department of Pathology, University of California, San Francisco, San Francisco, California. .,Diabetes Center, University of California, San Francisco, San Francisco, California.,Department of Medicine, University of California, San Francisco, San Francisco, California.,Lung Biology Center, University of California, San Francisco, San Francisco, California.,California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, California
Scott A Oakes Department of Pathology, University of California, San Francisco, San Francisco, California. .,Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.,Diabetes Center, University of California, San Francisco, San Francisco, California.,Department of Pathology, Biological Sciences Division, Pritzker School of Medicine, University of Chicago, Chicago, Illinois

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Gioelli N, Maione F, Camillo C, Ghitti M, Valdembri D, Morello N, Darche M, Zentilin L, Cagnoni G, Qiu Y, Giacca M, Giustetto M, Paques M, Cascone I, Musco G, Tamagnone L, Giraudo E, Serini G. A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent. Sci Transl Med 2019;10:10/442/eaah4807. [PMID: 29794061 DOI: 10.1126/scitranslmed.aah4807] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 11/20/2017] [Accepted: 04/26/2018] [Indexed: 12/12/2022]

Affiliation(s)

Noemi Gioelli Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
Federica Maione Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.,Department of Science and Drug Technology, University of Torino, 10125 Torino, Italy
Chiara Camillo Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
Michela Ghitti Biomolecular NMR Unit, IRCCS Ospedale San Raffaele, 20132 Milano, Italy
Donatella Valdembri Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
Noemi Morello Department of Neuroscience, University of Torino School of Medicine, 10126 Torino, Italy
Marie Darche Growth, Reparation and Tissue Regeneration Laboratory, ERL-CNRS 9215, University of Paris-Est, 94000 Créteil, France
Lorena Zentilin Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
Gabriella Cagnoni Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
Yaqi Qiu Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy.,Department of Science and Drug Technology, University of Torino, 10125 Torino, Italy
Mauro Giacca Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
Maurizio Giustetto Department of Neuroscience, University of Torino School of Medicine, 10126 Torino, Italy.,National Institute of Neuroscience-Italy, 10126 Torino, Italy
Michel Paques Vision Institute, Sorbonne University, UPMC University of Paris 06, INSERM, CNRS, 75012 Paris, France.,Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, 75012 Paris, France
Ilaria Cascone Growth, Reparation and Tissue Regeneration Laboratory, ERL-CNRS 9215, University of Paris-Est, 94000 Créteil, France
Giovanna Musco Biomolecular NMR Unit, IRCCS Ospedale San Raffaele, 20132 Milano, Italy
Luca Tamagnone Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy.,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy
Enrico Giraudo Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy. .,Department of Science and Drug Technology, University of Torino, 10125 Torino, Italy
Guido Serini Department of Oncology, University of Torino School of Medicine, 10060 Candiolo, Torino, Italy. .,Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Torino, Italy

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Jászai J, Schmidt MHH. Trends and Challenges in Tumor Anti-Angiogenic Therapies. Cells 2019;8:cells8091102. [PMID: 31540455 PMCID: PMC6770676 DOI: 10.3390/cells8091102] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 01/18/2023] Open

Mateus PAM, Kido LA, Silva RS, Cagnon VHA, Montico F. Association of anti-inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice. Prostate 2019;79:515-535. [PMID: 30585351 DOI: 10.1002/pros.23758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 11/29/2018] [Indexed: 12/22/2022]

Abstract

BACKGROUND

Chronic inflammation has been implicated in cancer etiology and angiogenesis is stimulated in this disease. In prostate, the crosstalk between malignant epithelial cells and their microenvironment is an essential step of tumorigenesis during which glandular stroma undergo changes designated as reactive stroma. Thus, the aim herewith was to evaluate the effects of associating anti-inflammatory and antiangiogenic therapies on cancer progression, correlating them with steroid hormone receptor (AR and ERα), reactive stroma (vimentin, αSMA, and TGF-β), and cell proliferation (PCNA) markers expression in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.

METHODS

TRAMP mice (12-week old) were divided into the groups: Control (TRCON): received the vehicles used for drug dilution; Celecoxib (TRCEL): received oral doses of the anti-inflammatory drug celecoxib (15 mg/kg) twice daily; Nintedanib (TRNTB): received oral doses of the antiangiogenic drug nintedanib (10 mg/kg) daily; Nintedanib+Celecoxib (TRNTCEL): received the combination of drugs. After 6 weeks, mice were euthanized and ventral prostate samples were harvested for morphological, immunohistochemical, and Western blotting analyses.

RESULTS

While celecoxib led to fibromuscular hypertrophy attenuation, nintedanib significantly reduced the incidence of well-differentiated adenocarcinoma (WDAC) foci in relation to controls, both when administered per se or in association to celecoxib. Furthermore, drug combination was associated with unique effects, including lower incidence of HGPIN lesions; lower AR stromal distribution; changes in ERα localization from epithelial nuclei to stroma as well as significant decrease of TGF-β levels and associated angiogenesis. In parallel, all treatments applied resulted in reduced inflammatory marker and vimentin (VIM) expression.

CONCLUSIONS

Celecoxib plus nintedanib is an effective antitumor combination against prostate cancer progression in TRAMP mice, showing remarkable efficacy in relation to isolated therapies. Importantly, this efficacy might be due to drug association effect on driving AR and mainly ERα distribution in the prostatic tissue towards benign patterns. In addition, celecoxib and nintedanib impaired the development of a stromal reaction by reducing the recruitment of reactive stroma cells and maintaining a normal smooth muscle cell-rich prostate stroma in TRAMP mice. Collectively, these findings pointed to the beneficial effects of combining anti-inflammatory and antiangiogenic strategies to prevent or delay prostatic tumorigenesis.

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Krug S, Abbassi R, Griesmann H, Sipos B, Wiese D, Rexin P, Blank A, Perren A, Haybaeck J, Hüttelmaier S, Rinke A, Gress TM, Michl P. Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. Int J Cancer 2019;143:1806-1816. [PMID: 29696624 DOI: 10.1002/ijc.31562] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 03/18/2018] [Accepted: 03/28/2018] [Indexed: 12/13/2022]

Abstract

Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

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Kochurova EV. Comparative Role of Matrixins in Diagnostics of Parotid Gland Tumors. Bull Exp Biol Med 2019;166:383-385. [PMID: 30617705 DOI: 10.1007/s10517-019-04355-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Indexed: 10/27/2022]

Moehler T, Hose D, Andrulis M, Seckinger A, Goldschmidt H. The Value of Anti-angiogenics in Multiple Myeloma Therapy. TUMOR ANGIOGENESIS 2019:639-658. [DOI: 10.1007/978-3-319-33673-2_34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]

Cuny T, de Herder W, Barlier A, Hofland LJ. Role of the tumor microenvironment in digestive neuroendocrine tumors. Endocr Relat Cancer 2018;25:R519-R544. [PMID: 30306777 DOI: 10.1530/erc-18-0025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Agarwal S, Muniyandi P, Maekawa T, Kumar DS. Vesicular systems employing natural substances as promising drug candidates for MMP inhibition in glioblastoma: A nanotechnological approach. Int J Pharm 2018;551:339-361. [PMID: 30236647 DOI: 10.1016/j.ijpharm.2018.09.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 09/14/2018] [Accepted: 09/15/2018] [Indexed: 12/16/2022]

Abstract

Glioblastoma multiforme (GBM), one of the most lethal Brain tumors, characterized by its high invasive nature and increased mortality rates forms a major bottleneck in transport of therapeutics across the Blood Brain Barrier (BBB). Matrix metalloproteinases (MMPs) are classified as enzymes, which are found to be up regulated in the Glioma tumor microenvironment and thus can be considered as a target for inhibition for curbing GBM. Many chemotherapeutics and techniques have been employed for inhibiting MMPs till now but all of them failed miserably and were withdrawn in clinical trials due to their inability in restricting the tumor growth or increasing the overall survival rates. Thus, the quest for finding the suitable MMP inhibitor is still on and there is a critical need for identification of novel compounds which can alter the BBB permeability, restrain tumor growth and prevent tumor recurrence. Currently, naturally derived substances are gaining widespread attention as tumor inhibitors and many studies have been reported by far highlighting their importance in restricting MMP expression thus serving as chemotherapeutics for cancer due to their minimal toxicity. These substances may serve as probable candidates for inhibiting MMP expression in GBM. However, targeting and delivering the inhibitor to its target site is an issue that needs to be overcome in order to attain maximum specificity and sustained release. The birth of nanotechnology served as a boon in delivering drugs to the most complicated areas thus paving way for Nano drug delivery. An efficient Nano carrier with ability to cross the BBB and competently kill the Glioma cells forms the prerequisite for GBM chemotherapy. Vesicular drug delivery systems are one such class of carriers, which have the capacity to release the drug at a predetermined rate at the target site thus minimizing any undesirable side effects. Exploiting vesicular systems as promising Nano drug carriers to formulate naturally derived substances, that can bypass the BBB and act as an inhibitor against MMPs in GBM is the main theme of this review.

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Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, Augustin HG, Bates DO, van Beijnum JR, Bender RHF, Bergers G, Bikfalvi A, Bischoff J, Böck BC, Brooks PC, Bussolino F, Cakir B, Carmeliet P, Castranova D, Cimpean AM, Cleaver O, Coukos G, Davis GE, De Palma M, Dimberg A, Dings RPM, Djonov V, Dudley AC, Dufton NP, Fendt SM, Ferrara N, Fruttiger M, Fukumura D, Ghesquière B, Gong Y, Griffin RJ, Harris AL, Hughes CCW, Hultgren NW, Iruela-Arispe ML, Irving M, Jain RK, Kalluri R, Kalucka J, Kerbel RS, Kitajewski J, Klaassen I, Kleinmann HK, Koolwijk P, Kuczynski E, Kwak BR, Marien K, Melero-Martin JM, Munn LL, Nicosia RF, Noel A, Nurro J, Olsson AK, Petrova TV, Pietras K, Pili R, Pollard JW, Post MJ, Quax PHA, Rabinovich GA, Raica M, Randi AM, Ribatti D, Ruegg C, Schlingemann RO, Schulte-Merker S, Smith LEH, Song JW, Stacker SA, Stalin J, Stratman AN, Van de Velde M, van Hinsbergh VWM, Vermeulen PB, Waltenberger J, Weinstein BM, Xin H, Yetkin-Arik B, Yla-Herttuala S, Yoder MC, Griffioen AW. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 2018;21:425-532. [PMID: 29766399 PMCID: PMC6237663 DOI: 10.1007/s10456-018-9613-x] [Citation(s) in RCA: 458] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

Affiliation(s)

Patrycja Nowak-Sliwinska Molecular Pharmacology Group, School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, University of Lausanne, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland. Translational Research Center in Oncohaematology, University of Geneva, Geneva, Switzerland.
Kari Alitalo Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
Elizabeth Allen Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium
Andrey Anisimov Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland
Alfred C Aplin Department of Pathology, University of Washington, Seattle, WA, USA
Robert Auerbach University of Wisconsin, Madison, WI, USA
Hellmut G Augustin European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany German Cancer Consortium, Heidelberg, Germany
David O Bates Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
Judy R van Beijnum Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
R Hugh F Bender Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
Gabriele Bergers Laboratory of Tumor Microenvironment and Therapeutic Resistance, Department of Oncology, VIB-Center for Cancer Biology, KU Leuven, Louvain, Belgium Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
Andreas Bikfalvi Angiogenesis and Tumor Microenvironment Laboratory (INSERM U1029), University Bordeaux, Pessac, France
Joyce Bischoff Vascular Biology Program and Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
Barbara C Böck European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany Division of Vascular Oncology and Metastasis Research, German Cancer Research Center, Heidelberg, Germany German Cancer Consortium, Heidelberg, Germany
Peter C Brooks Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA
Federico Bussolino Department of Oncology, University of Torino, Turin, Italy Candiolo Cancer Institute-FPO-IRCCS, 10060, Candiolo, Italy
Bertan Cakir Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
Peter Carmeliet Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
Daniel Castranova Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Anca M Cimpean Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
Ondine Cleaver Department of Molecular Biology, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
George Coukos Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
George E Davis Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine and Dalton Cardiovascular Center, Columbia, MO, USA
Michele De Palma School of Life Sciences, Swiss Federal Institute of Technology, Lausanne, Switzerland
Anna Dimberg Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Ruud P M Dings Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Valentin Djonov Institute of Anatomy, University of Bern, Bern, Switzerland
Andrew C Dudley Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA Emily Couric Cancer Center, The University of Virginia, Charlottesville, VA, USA
Neil P Dufton Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
Sarah-Maria Fendt Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology, Leuven, Belgium Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute, Leuven, Belgium
Napoleone Ferrara University of California, San Diego, La Jolla, CA, USA
Marcus Fruttiger Institute of Ophthalmology, University College London, London, UK
Dai Fukumura Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Bart Ghesquière Metabolomics Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium Department of Oncology, Metabolomics Expertise Center, KU Leuven, Leuven, Belgium
Yan Gong Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
Robert J Griffin Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Adrian L Harris Molecular Oncology Laboratories, Oxford University Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
Christopher C W Hughes Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
Nan W Hultgren Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
M Luisa Iruela-Arispe MCDB, University of California, Los Angeles, CA, USA
Melita Irving Ludwig Institute for Cancer Research, Department of Oncology, University of Lausanne, Lausanne, Switzerland
Rakesh K Jain Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Raghu Kalluri Department of Cancer Biology, Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Joanna Kalucka Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
Robert S Kerbel Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
Jan Kitajewski Department of Physiology and Biophysics, University of Illinois, Chicago, IL, USA
Ingeborg Klaassen Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Hynda K Kleinmann The George Washington University School of Medicine, Washington, DC, USA
Pieter Koolwijk Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
Elisabeth Kuczynski Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada
Brenda R Kwak Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
Koen Marien HistoGeneX, Antwerp, Belgium
Juan M Melero-Martin Department of Cardiac Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
Lance L Munn Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Roberto F Nicosia Department of Pathology, University of Washington, Seattle, WA, USA Pathology and Laboratory Medicine Service, VA Puget Sound Health Care System, Seattle, WA, USA
Agnes Noel Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
Jussi Nurro Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
Anna-Karin Olsson Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden
Tatiana V Petrova Department of oncology UNIL-CHUV, Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
Kristian Pietras Division of Translational Cancer Research, Department of Laboratory Medicine, Lund, Sweden
Roberto Pili Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
Jeffrey W Pollard Medical Research Council Centre for Reproductive Health, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
Mark J Post Department of Physiology, Maastricht University, Maastricht, The Netherlands
Paul H A Quax Einthoven Laboratory for Experimental Vascular Medicine, Department Surgery, LUMC, Leiden, The Netherlands
Gabriel A Rabinovich Laboratory of Immunopathology, Institute of Biology and Experimental Medicine, National Council of Scientific and Technical Investigations (CONICET), Buenos Aires, Argentina
Marius Raica Department of Microscopic Morphology/Histology, Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
Anna M Randi Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, UK
Domenico Ribatti Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy National Cancer Institute "Giovanni Paolo II", Bari, Italy
Curzio Ruegg Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
Reinier O Schlingemann Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
Stefan Schulte-Merker Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
Lois E H Smith Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
Jonathan W Song Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
Steven A Stacker Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre and The Sir Peter MacCallum, Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
Jimmy Stalin Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU, Münster, Germany
Amber N Stratman Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Maureen Van de Velde Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Liège, Belgium
Victor W M van Hinsbergh Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
Peter B Vermeulen HistoGeneX, Antwerp, Belgium Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus & University of Antwerp, Antwerp, Belgium
Johannes Waltenberger Medical Faculty, University of Münster, Albert-Schweitzer-Campus 1, Münster, Germany
Brant M Weinstein Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Hong Xin University of California, San Diego, La Jolla, CA, USA
Bahar Yetkin-Arik Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Seppo Yla-Herttuala Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland
Mervin C Yoder Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Arjan W Griffioen Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

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Fathy M, Awale S, Nikaido T. Phosphorylated Akt Protein at Ser473 Enables HeLa Cells to Tolerate Nutrient-Deprived Conditions. Asian Pac J Cancer Prev 2017;18:3255-3260. [PMID: 29286216 PMCID: PMC5980880 DOI: 10.22034/apjcp.2017.18.12.3255] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open