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The role of progenitor cell recruitment in aggressive tumor recurrence following radiofrequency ablation (RFA)

Projectomschrijving

In Nederland wordt iederjaar bij 10.000 nieuwe patiënten dikkedarmkanker ontdekt. Bij 50-60% van deze patiënten zullen uiteindelijk uitzaaiingen in de lever ontstaan. Voor slechts 20-30%  van de patiënten is het chirurgisch verwijderen van deze uitzaaiingen  een behandeloptie. Een alternatieve behandeling voor patiënten bij wie de tumor niet chirurgisch verwijderd kan worden is radiofrequentie  ablatie (RFA), waarbij de tumor met behulp van elektrische stroom wordt weggebrand. Helaas komen bij veel van de behandelde patiënten de uitzaaingen echter terug. Eerder is aangetoond dat RFA de uitgroei  van microscopisch kleine uitzaaiingen bevorderd, die  zeer snel indringen in het omliggende weefsel. Drs. Nijkamp gaat onderzoeken waarom RFA er  voor zorgt dat de microscopisch kleine uitzaaiingen kunnen indringen in het omliggende weefsel, zodat in de toekomst de behandeling kan worden verbeterd. 

Producten

Titel: Prolonged portal triad clamping during liver surgery for colorectal liver metastases is associated with decreased time to hepatic tumor recurrence
Auteur: Maarten W. Nijkamp Jarmila D.W. van der Bilt Nikol Snoeren Frederik J.H. Hoogwater Winan J. van Houdt I. Quintus Molenaar Onno Kranenburg Richard van Hillegersberg Inne H.M. Borel Rinkes
Magazine: European Journal of Surgical Oncology
Titel: Radiofrequency ablation of colorectal liver metastases induces an inflammatory response in distant hepatic metastases but not in local accelerated outgrowth
Auteur: Maarten W. Nijkamp1 Alie Borren1 Klaas M. Govaert1 Frederik J.H. Hoogwater1 I.Quintus Molenaar1 Paul J. van Diest2 Onno Kranenburg1 Inne H.M. Borel Rinkes1 Departments of 1Surgery and 2Pathology University Medical Center Utrecht, Utrecht, The Netherlands
Magazine: Journal of surgical oncology
Titel: Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells
Auteur: Frederik J.H. Hoogwater1 Maarten W. Nijkamp1* Niels Smakman1* Ernst J.A. Steller1 Benjamin L. Emmink1 B. Florien Westendorp1 Danielle A.E. Raats1 Martin R. Sprick2 Uta Schaefer3 Winan J. van Houdt1 Menno T. de Bruijn1 Ron C.J. Schackmann1 Patrick W.B. Derksen1 Jan-Paul Medema3 Henning Walczak4 Inne H.M. Borel Rinkes1 Onno Kranenburg1 * these authors contributed equally Departments of 1Surgery and 2Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands 3Laboratory of Experi
Magazine: Gastroenterology
Titel: CD95 is a key mediator of invasion and accelerated outgrowth of colorectal liver metastases following radiofrequency ablation
Auteur: Maarten W. Nijkamp* Frederik J.H. Hoogwater* Ernst J.A. Steller B. Florien Westendorp Taco A. van der Meulen Martijn W.H. Leenders Inne H.M. Borel Rinkes Onno Kranenburg * these authors contributed equally
Magazine: Journal of Hepatology
Titel: Surgery-stimulated tumor growth.
Auteur: Maarten W. Nijkamp

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Samenvatting van de aanvraag

In the Netherlands, 10.000 new cases of colorectal carcinoma are diagnosed each year. Eventually, liver metastases will form in 50-60% of these patients. Surgical resection of liver metastases is potentially curative, but this is only applicable in approximately 10-30% of cases. For patients with non-resectable liver metastases, radiofrequency ablation (RFA) represents an alternative local treatment option. RFA is based on local destruction of (tumor)tissue with a probe that uses alternating current to generate heat. A disadvantage of this therapy is the high rate of local tumor recurrence, which is observed in up to 60% of the treated patients. Our results in a murine model show that RFA stimulates the outgrowth of microscopically small metastases (micrometastases) that are localized immediately adjacent to the generated necrotic lesion (transition zone (TZ)) by approximately 4-5 fold. This outgrowth is characterized by a rapid and dramatic phenotypic change in the tumor cells: while micrometastases in the reference tissue (i.e. normal liver parenchyma) grow as compact spheres with sharply demarcated edges, those in the TZ display an aggressive and invasive phenotype with trails of tumor cells detaching from the metastases and invading the surrounding tissue. This is observed as early as 4-6 hours following RFA treatment. The TZ is further characterized by immediate disturbances in the microcirculation, chronic hypoxia and stabilization of Hypoxia Inducible Factor-1alpha (HIF-1alpha), HIF-2alpha, and HIF-target genes for up to 7 days following RFA treatment. Thus, invasion of micrometastases following RFA in the TZ is strongly associated with long-lasting local tissue hypoxia. In line with this, we observed the formation of large functional macrovessels in the transition zone from 3-5 days following RFA, but these vessels were not associated with invading tumor cells. Local tumor cell invasion is supported by bone marrow-derived progenitor cells (BMDPCs) and mesenchymal stem cells (MSCs). Both cell types are actively recruited to regions of hypoxia, to injured tissue as well as to tumors. Recently, it was shown that local invasion of colorectal tumors depends on CCL9-dependent recruitment of a subpopulation of immature BMD myeloid cells expressing CCR1[1]. Conversely, tumor-associated mesenchymal stem cells stimulate tumor invasion and metastasis formation by producing CCL5 acting on the CCR5 receptor expressed on (breast) tumor cells[2]. These examples show how reciprocal interactions between tumor cells and (recruited) stromal cells can influence tumor invasion. Our aim is to identify critical chemokines/cytokines and recruited progenitor cells that mediate rapid invasion and growth stimulation of micrometastases following RFA treatment in mice. To this end we will identify the distinct types of progenitor cells that are recruited to RFA-generated lesions and nearby micrometastases within 6 hours. We will make use of mice with transplanted Green Fluorescent Protein (GFP)-expressing bone marrow or GFP-expressing mesenchymal stem cells. The tumor cells in these experiments express the red fluorescent protein mCherry. The recruited GFP-positive cells will be analyzed for their cell surface marker profile by FACS analysis of tissue-derived single cell suspensions and by immunofluorescence analysis on frozen tissue sections. The latter approach will also identify potential physical interactions between recruited (green) progenitor cells and invasive (red) tumor cells. Using microarray gene expression profiles of tissue that surrounds the RFA-generated lesion, we will identify changes in the expression of cytokines, chemokines and growth factors that may cause the recruitment of progenitor cells. The expression of the genes that have changed following RFA will be validated by RT-PCR and/or ELISA of RNA and protein extracts from the tissue that surrounds the RFA-generated lesion. To assess whether the local changes in expression are reflected in changes in blood levels, blood samples isolated from RFA-treated mice will be analysed by ELISA for the level of the identified cytokines, chemokines and growth factors. Finally, we will analyze how selective neutralization of the identified cytokines, chemokines and/or cell surface markers affects the recruitment of progenitor cells, tumor cell invasion and accelerated tumor growth following RFA. With the proposed studies we hope to identify critical mediators of RFA-induced invasion and growth stimulation of micrometastases. These mediators may represent novel targets for adjuvant therapy following RFA treatment of colorectal liver metastases.

Onderwerpen

Kenmerken

Projectnummer:
92003534
Looptijd: 100%
Looptijd: 100 %
2009
2012
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. I.H.M. Borel Rinkes MD PhD
Verantwoordelijke organisatie:
Universitair Medisch Centrum Utrecht