Preclinical targeting of the tumor microenvironment: Possibilities and consequences

Marlous Arjaans

Preclinical targeting of the tumor microenvironment: Possibilities and consequences

Marlous Arjaans

Onderzoeksoutput: Thesis fully internal (DIV)

1464 Downloads (Pure)

Samenvatting

Gemetastaseerde ziekte is momenteel de hoofdoorzaak van alle aan kanker gerelateerde sterfte. Dit onderstreept het belang van het vinden van nieuwe behandelstrategieën. Onlangs bleek dat het normale weefsel dat de tumor omgeeft, de tumormicro-omgeving, een belangrijke rol speelt bij tumorgroei en metastasering. Door nieuwe behandelopties te richten tegen zowel de kankercellen als de tumormicro-omgeving, kan de effectiviteit van huidige therapieën mogelijk worden verbeterd. Voor de ontwikkeling van een dergelijke nieuwe behandeloptie, is het noodzakelijk om moleculaire factoren in de tumormicro-omgeving te identificeren. Twee potentiële factoren zijn transforming growth factor (TGF)-β en vascular endothelial growth factor (VEGF).

In preklinische modellen bestaande uit stromale- en borstkankercellen wordt de tumor met zijn micro-omgeving nagebootst. Deze in vitro en in vivo modellen laten zien dat stromale cellen nodig zijn voor het TGF-β gemedieerde anti-borstkankereffect van het bisfosfonaat zoledronaat. Daarnaast wordt de preklinische ontwikkeling van een TGF-β tracer beschreven. Bij deze techniek wordt een radioactief gelabeld antilichaam afgebeeld met positron emissie tomografie (PET). Middels deze TGF-β tracer kon de aanwezigheid van TGF-β in tumoren worden afgebeeld.
Voor VEGF werd het effect van anti-VEGF therapie op geneesmiddelopname geëvalueerd met behulp van PET beeldvorming. Anti-VEGF therapie vermindert de opname van andere geneesmiddelen in twee verschillende preklinische modellen.

Concluderend beschrijft dit proefschrift preklinisch onderzoek naar de mogelijkheden en consequenties van therapieën gericht op factoren in de tumormicro-omgeving.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	de Vries, Liesbeth, Supervisor Schröder, Carolien, Co-supervisor Timmer-Bosscha, Hetty, Co-supervisor Lub-de Hooge, Marjolijn, Co-supervisor
Datum van toekenning	15-apr-2015
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Status	Published - 2015

Toegang tot document

Title and contents Final publisher's version, 186 KB
Chapter 1Final publisher's version, 222 KB
Chapter 2Final publisher's version, 5,52 MB
Chapter 3Final publisher's version, 4,73 MB
Chapter 4Final publisher's version, 2,4 MB
Chapter 5AFinal publisher's version, 3,41 MB
Chapter 5BFinal publisher's version, 226 KB
Chapter 6Final publisher's version, 392 KB
Chapter 7Final publisher's version, 286 KB
Chapter 8Final publisher's version, 254 KB
Acknowledgements Final publisher's version, 227 KB
Complete dissertationFinal publisher's version, 15,7 MB
PropositionsFinal publisher's version, 123 KB

Citeer dit

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title = "Preclinical targeting of the tumor microenvironment: Possibilities and consequences",

abstract = "Metastatic disease is currently the main cause of all cancer induced deaths. Therefore, there is an ongoing search for new treatment strategies that may increase treatment effects. However, the importance of the tumor microenvironment as a contributor to tumor growth and metastatic disease has become more evident. This provides the rational for targeting not only the cancer cells, but also the tumor microenvironment, in order to aim to improve cancer treatment. To enable accurate targeting, it is essential to identify key targets present in the tumor microenvironment. Two potential targets present in the tumor microenvironment are transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF). The tumor and its microenvironment are reproduced in preclinical models consisting of both stromal and cancer cells. These in vitro and in vivo models show that stromal cells are needed to exert the TGF-β mediated anti-breast cancer effect of the bisphosphonate zoledronic acid. In addition, the preclinical development of a TGF-β tracer is described. With this technique, a radiolabeled antibody can be depicted with the help of positron emission tomography (PET). With the use of the TGF-β tracer it was possible to portray the presence of TGF-β in tumors. For VEGF, the effect of anti-VEGF therapy on tumor uptake of drugs was evaluated with the help of PET imaging. Anti-VEGF therapy reduced tumor uptake of other drugs in two preclinical models.In conclusion, this thesis describes the possibilities and consequences of targeting factors present in the tumor microenvironment.",

author = "Marlous Arjaans",

year = "2015",

language = "English",

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TY - THES

T1 - Preclinical targeting of the tumor microenvironment

T2 - Possibilities and consequences

AU - Arjaans, Marlous

PY - 2015

Y1 - 2015

N2 - Metastatic disease is currently the main cause of all cancer induced deaths. Therefore, there is an ongoing search for new treatment strategies that may increase treatment effects. However, the importance of the tumor microenvironment as a contributor to tumor growth and metastatic disease has become more evident. This provides the rational for targeting not only the cancer cells, but also the tumor microenvironment, in order to aim to improve cancer treatment. To enable accurate targeting, it is essential to identify key targets present in the tumor microenvironment. Two potential targets present in the tumor microenvironment are transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF). The tumor and its microenvironment are reproduced in preclinical models consisting of both stromal and cancer cells. These in vitro and in vivo models show that stromal cells are needed to exert the TGF-β mediated anti-breast cancer effect of the bisphosphonate zoledronic acid. In addition, the preclinical development of a TGF-β tracer is described. With this technique, a radiolabeled antibody can be depicted with the help of positron emission tomography (PET). With the use of the TGF-β tracer it was possible to portray the presence of TGF-β in tumors. For VEGF, the effect of anti-VEGF therapy on tumor uptake of drugs was evaluated with the help of PET imaging. Anti-VEGF therapy reduced tumor uptake of other drugs in two preclinical models.In conclusion, this thesis describes the possibilities and consequences of targeting factors present in the tumor microenvironment.

AB - Metastatic disease is currently the main cause of all cancer induced deaths. Therefore, there is an ongoing search for new treatment strategies that may increase treatment effects. However, the importance of the tumor microenvironment as a contributor to tumor growth and metastatic disease has become more evident. This provides the rational for targeting not only the cancer cells, but also the tumor microenvironment, in order to aim to improve cancer treatment. To enable accurate targeting, it is essential to identify key targets present in the tumor microenvironment. Two potential targets present in the tumor microenvironment are transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF). The tumor and its microenvironment are reproduced in preclinical models consisting of both stromal and cancer cells. These in vitro and in vivo models show that stromal cells are needed to exert the TGF-β mediated anti-breast cancer effect of the bisphosphonate zoledronic acid. In addition, the preclinical development of a TGF-β tracer is described. With this technique, a radiolabeled antibody can be depicted with the help of positron emission tomography (PET). With the use of the TGF-β tracer it was possible to portray the presence of TGF-β in tumors. For VEGF, the effect of anti-VEGF therapy on tumor uptake of drugs was evaluated with the help of PET imaging. Anti-VEGF therapy reduced tumor uptake of other drugs in two preclinical models.In conclusion, this thesis describes the possibilities and consequences of targeting factors present in the tumor microenvironment.

M3 - Thesis fully internal (DIV)

PB - University of Groningen

CY - [Groningen]

ER -