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Article: The Matrix Reloaded-The Role of the Extracellular Matrix in Cancer.

Raskov, Hans / Gaggar, Shruti / Tajik, Asma / Orhan, Adile / Gögenur, Ismail

2023 Volume 15, Issue 7

Abstract: As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in ... ...

Abstract	As the core component of all organs, the extracellular matrix (ECM) is an interlocking macromolecular meshwork of proteins, glycoproteins, and proteoglycans that provides mechanical support to cells and tissues. In cancer, the ECM can be remodelled in response to environmental cues, and it controls a plethora of cellular functions, including metabolism, cell polarity, migration, and proliferation, to sustain and support oncogenesis. The biophysical and biochemical properties of the ECM, such as its structural arrangement and being a reservoir for bioactive molecules, control several intra- and intercellular signalling pathways and induce cytoskeletal changes that alter cell shapes, behaviour, and viability. Desmoplasia is a major component of solid tumours. The abnormal deposition and composition of the tumour matrix lead to biochemical and biomechanical alterations that determine disease development and resistance to treatment. This review summarises the complex roles of ECM in cancer and highlights the possible therapeutic targets and how to potentially remodel the dysregulated ECM in the future. Furthering our understanding of the ECM in cancer is important as the modification of the ECM will probably become an important tool in the characterisation of individual tumours and personalised treatment options.
Language	English
Publishing date	2023-03-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15072057
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Article: Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy.

Raskov, Hans / Orhan, Adile / Gaggar, Shruti / Gögenur, Ismail

Oncogenesis

2022 Volume 11, Issue 1, Page(s) 22

Abstract: Neutrophils are central mediators of innate and adaptive immunity and first responders to tissue damage. Although vital to our health, their activation, function, and resolution are critical to preventing chronic inflammation that may contribute to ... ...

Abstract	Neutrophils are central mediators of innate and adaptive immunity and first responders to tissue damage. Although vital to our health, their activation, function, and resolution are critical to preventing chronic inflammation that may contribute to carcinogenesis. Cancers are associated with the expansion of the neutrophil compartment with an escalation in the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the peripheral circulation and tumor microenvironment. Although phenotypically similar to classically activated neutrophils, PMN-MDSC is pathologically activated and immunosuppressive in nature. They dynamically interact with other cell populations and tissue components and convey resistance to anticancer therapies while accelerating disease progression and metastatic spread. Cancer-associated neutrophilia and tumor infiltration of neutrophils are significant markers of poor outcomes in many cancers. Recently, there has been significant progress in the identification of molecular markers of PMN-MDSC providing insights into the central role of PMN-MDSC in the local tumor microenvironment as well as the systemic immune response in cancer. Further advances in sequencing and proteomics techniques will improve our understanding of their diverse functionalities and the complex molecular mechanisms at play. Targeting PMN-MDSC is currently one of the major focus areas in cancer research and several signaling pathways representing possible treatment targets have been identified. Positive results from preclinical studies clearly justify the current investigation in drug development and thus novel therapeutic strategies are being evaluated in clinical trials. In this review, we discuss the involvement of PMN-MDSC in cancer initiation and progression and their potential as therapeutic targets and clinical biomarkers in different cancers.
Language	English
Publishing date	2022-05-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2674437-5
ISSN	2157-9024
ISSN	2157-9024
DOI	10.1038/s41389-022-00398-3
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Article ; Online: Metabolic switch in cancer - Survival of the fittest.

Raskov, Hans / Gaggar, Shruti / Tajik, Asma / Orhan, Adile / Gögenur, Ismail

European journal of cancer (Oxford, England : 1990)

2022 Volume 180, Page(s) 30–51

Abstract: Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring ... ...

Abstract	Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.
MeSH term(s)	Humans ; Neoplasms/drug therapy ; Energy Metabolism ; Glycolysis ; Mutation
Language	English
Publishing date	2022-11-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2022.11.025
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Article: Cancer-Associated Fibroblasts and Tumor-Associated Macrophages in Cancer and Cancer Immunotherapy.

Raskov, Hans / Orhan, Adile / Gaggar, Shruti / Gögenur, Ismail

Frontiers in oncology

2021 Volume 11, Page(s) 668731

Abstract: Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell ... ...

Abstract	Our understanding of the tumor microenvironment (TME), including the interplay between tumor cells, stromal cells, immune cells, and extracellular matrix components, is mandatory for the innovation of new therapeutic approaches in cancer. The cell-cell communication within the TME plays a pivotal role in the evolution and progression of cancer. Cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) are major cell populations in the stroma of all solid tumors and often exert protumorigenic functions; however, the origin and precise functions of CAF and TAM are still incompletely understood. CAF and TAM hold significant potential as therapeutic targets to improve outcomes in oncology when combined with existing therapies. The regulation of CAF/TAM communication and/or their differentiation could be of high impact for improving the future targeted treatment strategies. Nevertheless, there is much scope for research and innovation in this field with regards to the development of novel drugs. In this review, we elaborate on the current knowledge on CAF and TAM in cancer and cancer immunotherapy. Additionally, by focusing on their heterogenous functions in different stages and types of cancer, we explore their role as potential therapeutic targets and highlight certain aspects of their functions that need further research.
Language	English
Publishing date	2021-05-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2021.668731
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Article ; Online: [No title information]

Orhan, Adile / Mørup, Sara / Poulsen, Laurids Østergaard / Pfeiffer, Per / Qvortrup, Camilla / Gögenur, Ismail

Ugeskrift for laeger

2023 Volume 185, Issue 51

Abstract: In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch- ... ...

Title translation	The role of immunotherapy in the treatment of colorectal cancer.
Abstract	In Denmark, around 4,500 people are diagnosed with colorectal cancer (CRC) annually. This review investigates that while the efficacy of immunotherapy in CRC is still being studied, immunotherapy is currently only indicated in the treatment of mismatch-repair deficient (dMMR) metastatic CRC, which accounts for 10-15% of patients. Recent studies indicate high rates of pathologic response in dMMR CRC treated with pre-operative immunotherapy while large-scale studies on novel immunotherapy combinations are ongoing.
MeSH term(s)	Humans ; Immunotherapy ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/therapy ; Colorectal Neoplasms/pathology ; Colonic Neoplasms ; Rectal Neoplasms
Language	Danish
Publishing date	2023-12-01
Publishing country	Denmark
Document type	Review ; English Abstract ; Journal Article
ZDB-ID	124102-3
ISSN	1603-6824 ; 0041-5782
ISSN (online)	1603-6824
ISSN	0041-5782
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Article ; Online: Myocardial injury and long-term oncological outcomes in patients undergoing surgery for colorectal cancer.

Zahid, Jawad Ahmad / Orhan, Adile / Hadi, Noor Al-Huda / Ekeloef, Sarah / Gögenur, Ismail

International journal of colorectal disease

2023 Volume 38, Issue 1, Page(s) 234

Abstract: Purpose: Myocardial injury after noncardiac surgery (MINS) is associated with increased mortality and postoperative complications. In patients with colorectal cancer (CRC), postoperative complications are a risk factor for cancer recurrence and disease- ... ...

Abstract	Purpose: Myocardial injury after noncardiac surgery (MINS) is associated with increased mortality and postoperative complications. In patients with colorectal cancer (CRC), postoperative complications are a risk factor for cancer recurrence and disease-free survival. This study investigates the association between MINS and long-term oncological outcomes in patients with CRC in an ERAS setting. Methods: This retrospective cohort study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017. Patients undergoing CRC surgery were included if troponin was measured twice after surgery. Outcomes were all-cause mortality, recurrence, and disease-free survival within five years of surgery. Results: Among 586 patients, 42 suffered MINS. After five years, 36% of patients with MINS and 26% without MINS had died, p = 0.15. When adjusted for sex, age and UICC, the hazard ratio (aHR) for 1-year all-cause mortality, recurrence, and disease-free survival were 2.40 [0.93-6.22], 1.47 [0.19-11.29], and 2.25 [0.95-5.32] for patients with MINS compared with those without, respectively. Further adjusting for ASA status, performance status, smoking, and laparotomies, the aHR for 3- and 5-year all-cause mortality were 1.05 [0.51-2.15] and 1.11 [0.62-1.99], respectively. Similarly, the aHR for 3- and 5-year recurrence were 1.38 [0.46-4.51], and 1.49 [0.56-3.98] and for 3- and 5-year disease-free survival the aHR were 1.19 [0.63-2.23], and 1.19 [0.70-2.03]. Conclusion: In absolute numbers, we found no difference in all-cause mortality and recurrence in patients with and without MINS. In adjusted Cox regression analyses, the hazard was increased for all-cause mortality, recurrence, and disease-free survival in patients with MINS without reaching statistical significance.
MeSH term(s)	Humans ; Retrospective Studies ; Disease-Free Survival ; Progression-Free Survival ; Postoperative Complications/etiology ; Colorectal Neoplasms/surgery
Language	English
Publishing date	2023-09-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	84975-3
ISSN	1432-1262 ; 0179-1958
ISSN (online)	1432-1262
ISSN	0179-1958
DOI	10.1007/s00384-023-04528-0
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Article ; Online: Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery.

Raskov, Hans / Orhan, Adile / Salanti, Ali / Gögenur, Ismail

International journal of cancer

2020 Volume 146, Issue 12, Page(s) 3244–3255

Abstract: The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and ... ...

Abstract	The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.
MeSH term(s)	Animals ; Cell Proliferation ; Cell Survival ; Disease Models, Animal ; Exosomes/immunology ; Exosomes/pathology ; Humans ; Neoplasm Seeding ; Neoplasm, Residual/blood ; Neoplasm, Residual/pathology ; Neoplasms/blood ; Neoplasms/pathology ; Neoplasms/prevention & control ; Neoplasms/surgery ; Neoplastic Cells, Circulating/immunology ; Neoplastic Cells, Circulating/pathology ; Neoplastic Stem Cells/immunology ; Neoplastic Stem Cells/pathology ; Surgical Procedures, Operative/adverse effects ; Tumor Microenvironment/immunology
Language	English
Publishing date	2020-01-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.32820
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Article ; Online: Natural Killer Cells in Cancer and Cancer Immunotherapy.

Raskov, Hans / Orhan, Adile / Salanti, Ali / Gaggar, Shruti / Gögenur, Ismail

Cancer letters

2021 Volume 520, Page(s) 233–242

Abstract: The detection and killing of neoplastic cells require coordination of a variety of antitumor effector cells. Natural killer (NK) cells of the innate immune system are at the forefront of the body's defense systems and evidence suggests that the ... ...

Abstract	The detection and killing of neoplastic cells require coordination of a variety of antitumor effector cells. Natural killer (NK) cells of the innate immune system are at the forefront of the body's defense systems and evidence suggests that the infiltration and cytotoxicity of NK cells in the cancer tissue influence treatment efficacy and survival. As powerful effectors in the anticancer immune response, NK cells rapidly recognize and kill transformed cells with little reactivity against healthy self-tissues, which highlights their potential role in cancer immunotherapy. Modern immunotherapeutic approaches include immune checkpoint inhibitors to revitalize dysfunctional T cells and adoptive cell transfer using CD8
MeSH term(s)	CD8-Positive T-Lymphocytes/immunology ; Humans ; Immunotherapy ; Immunotherapy, Adoptive/trends ; Killer Cells, Natural/immunology ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/therapeutic use
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2021-07-22
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2021.07.032
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Article ; Online: Myocardial Injury After Colorectal Cancer Surgery and Postoperative 90-Day Mortality and Morbidity: A Retrospective Cohort Study.

Zahid, Jawad A / Orhan, Adile / Ekeloef, Sarah / Gögenur, Ismail

Diseases of the colon and rectum

2021 Volume 64, Issue 12, Page(s) 1531–1541

Abstract: Background: Myocardial injury after noncardiac surgery is a strong predictor of 30-day mortality and morbidity.: Objective: The purpose of this study was to examine the incidence of myocardial injury in patients undergoing colorectal cancer surgery ... ...

Abstract	Background: Myocardial injury after noncardiac surgery is a strong predictor of 30-day mortality and morbidity. Objective: The purpose of this study was to examine the incidence of myocardial injury in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol and its association with 90-day mortality and morbidity. Design: This is a retrospective cohort study. Setting: This study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017. Patients: Adult patients undergoing colorectal cancer surgery were included if troponin was measured at least twice during the first 7 days after surgery. The patients were followed for 90 days. Main outcome measures: Myocardial injury was defined as an elevated troponin I measurement (>45 ng/L) without evidence of a nonischemic origin causing the elevation. Ninety-day mortality and complications were assessed. Results: A total of 586 patients were included of which 42 were diagnosed with myocardial injury. Thirteen patients (2%) died within 90 days of surgery. There was no significant difference in 90-day mortality between patients with and without myocardial injury (5% (2/42) versus 2% (11/544); p = 0.24). We found a higher incidence of postoperative complications within 90 days of surgery in the myocardial injury group than in the nonmyocardial injury group (43% (18/42) versus 20% (107/544); p < 0.01). We found a significant difference between the myocardial injury group and nonmyocardial injury group in terms of medical complications (33% (14/42) versus 9% (50/544); p < 0.01) but not surgical complications (19% (8/42) versus 16% (85/544); p = 0.56). Myocardial injury was an independent predictor of postoperative complications within 90 days of surgery (adjusted OR, 2.69; 95% CI, 1.31-5.55). Limitations: This study was limited by its retrospective design. Conclusion: Myocardial injury occurs frequently in patients undergoing colorectal cancer surgery in an enhanced recovery after surgery protocol. Patients with myocardial injury did not have a significantly higher 90-day mortality but had higher risk of 90-day postoperative complications than patients without myocardial injury. Future research should examine the prevention and treatment of myocardial injury. See Video Abstract at http://links.lww.com/DCR/B692. Lesin miocrdica despus de la ciruga de cncer colorrectal y mortalidad y morbilidad posoperatorias a los das un estudio de cohorte retrospective: ANTECEDENTES:La lesión del miocardio después de una cirugía no cardíaca es un fuerte predictor de mortalidad y morbilidad a los 30 días.OBJETIVO:El propósito fue examinar la incidencia de lesión miocárdica en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía y su asociación con la mortalidad y morbilidad a los 90 días.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Realizado en el Hospital Universitario de Zelanda, Dinamarca, entre junio de 2015 y julio de 2017.PACIENTES:Se incluyeron pacientes adultos sometidos a cirugía de cáncer colorrectal, si la troponina se midió al menos dos veces durante los primeros siete días después de la cirugía. Los pacientes fueron seguidos durante 90 días.PRINCIPALES MEDIDAS DE RESULTADO:La lesión miocárdica se definió como una medición de troponina I elevada (> 45 ng / l) sin evidencia de una etiología no isquémica que causara la elevación. Se evaluaron la mortalidad y las complicaciones a los noventa días.RESULTADOS:Se incluyeron un total de 586 pacientes, de los cuales 42 fueron diagnosticados de lesión miocárdica. Trece pacientes (2%) murieron dentro de los 90 días posteriores a la cirugía. No hubo diferencias significativas en la mortalidad a 90 días entre los pacientes con y sin lesión del miocardio, 5% [2/42] versus 2% [11/544], p = 0,24. Encontramos una mayor incidencia de complicaciones posoperatorias dentro de los 90 días de la cirugía en el grupo de lesión miocárdica en comparación con el grupo de lesión no miocárdica, 43% [18/42] versus 20% [107/544], p <0,01. Encontramos una diferencia significativa entre el grupo de lesión miocárdica y el grupo de lesión no miocárdica en términos de complicaciones médicas (33% [14/42] versus 9% [50/544]; p <0,01) pero no complicaciones quirúrgicas (19% [8/42] versus 16% [85/544]; p = 0,56). La lesión miocárdica fue un predictor independiente de complicaciones posoperatorias dentro de los 90 días posteriores a la cirugía (razón de probabilidades ajustada: 2,69; intervalo de confianza del 95%: 1,31 - 5,55).LIMITACIONES:Limitado por su diseño retrospectivo.CONCLUSIÓN:La lesión del miocardio ocurre con frecuencia en pacientes sometidos a cirugía de cáncer colorrectal en un protocolo de recuperación mejorada después de la cirugía. Los pacientes con lesión miocárdica no tuvieron una mortalidad significativamente mayor a los 90 días, pero tuvieron un mayor riesgo de complicaciones posoperatorias a los 90 días en comparación con los pacientes sin lesión miocárdica. Las investigaciones futuras deben examinar la prevención y el tratamiento de la lesión miocárdica. Consulte Video Resumen en http://links.lww.com/DCR/B692.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Case-Control Studies ; Colorectal Neoplasms/complications ; Colorectal Neoplasms/surgery ; Colorectal Surgery/adverse effects ; Denmark/epidemiology ; Enhanced Recovery After Surgery/standards ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Morbidity/trends ; Myocardium/metabolism ; Myocardium/pathology ; Postoperative Complications/epidemiology ; Postoperative Complications/mortality ; Predictive Value of Tests ; Retrospective Studies ; Troponin/blood
Chemical Substances	Troponin
Language	English
Publishing date	2021-09-03
Publishing country	United States
Document type	Journal Article ; Webcast
ZDB-ID	212581-x
ISSN	1530-0358 ; 0012-3706
ISSN (online)	1530-0358
ISSN	0012-3706
DOI	10.1097/DCR.0000000000002061
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Article: Electroporation and Immunotherapy-Unleashing the Abscopal Effect.

Justesen, Tobias Freyberg / Orhan, Adile / Raskov, Hans / Nolsoe, Christian / Gögenur, Ismail

Cancers

2022 Volume 14, Issue 12

Abstract: The discovery of electroporation in 1968 has led to the development of electrochemotherapy (ECT) and irreversible electroporation (IRE). ECT and IRE have been established as treatments of cutaneous and subcutaneous tumors and locally advanced pancreatic ... ...

Abstract	The discovery of electroporation in 1968 has led to the development of electrochemotherapy (ECT) and irreversible electroporation (IRE). ECT and IRE have been established as treatments of cutaneous and subcutaneous tumors and locally advanced pancreatic cancer, respectively. Interestingly, the treatment modalities have been shown to elicit immunogenic cell death, which in turn can induce an immune response towards the tumor cells. With the dawn of the immunotherapy era, the potential of combining ECT and IRE with immunotherapy has led to the launch of numerous studies. Data from the first clinical trials are promising, and new combination regimes might change the way we treat tumors characterized by low immunogenicity and high levels of immunosuppression, such as melanoma and pancreatic cancer. In this review we will give an introduction to ECT and IRE and discuss the impact on the immune system. Additionally, we will present the results of clinical and preclinical trials, investigating the combination of electroporation modalities and immunotherapy.
Language	English
Publishing date	2022-06-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14122876
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