Cancer stem cells and epithelial-to-mesenchymal transition in lung cancer

Milind M. Pore

Cancer stem cells and epithelial-to-mesenchymal transition in lung cancer

Milind M. Pore

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Longkanker is een veel voorkomende ziekte met vaak een slechte prognose. Dit komt met name doordat de ziekte meestal in een vergevorderd, uitgezaaid stadium ontdekt wordt. De kankerstamcel theorie zegt dat de kankerstamcellen (CSC), een klein percentage van de tumorcellen, verantwoordelijk is voor uitgezaaide ziekte (metastases) en resistentie voor behandeling. Ook wordt verondersteld dat een differentiatie proces, epitheliale naar mesenchymale transitie (EMT) genoemd, bijdraagt tot een aggresiever karakter van tumorcellen en verspreiding ervan door het lichaam via de bloedbaan. Tumorcellen in de bloedbaan worden circulerende tumorcellen (CTC) genoemd.
In dit proefschrift hebben we bovenstaande theorie en processen onderzocht bij kleincellig longkanker, met name in relatie tot uitgezaaide ziekte en resistentie voor behandeling. We vonden geen verschillen in EMT eigenschappen, maar wel een toename van CSC eigenschappen tijdens ziekteprogressie in een celkweekmodel. In een eerdere studie bleken hoge aantallen CTC in het bloed voorspellend te zijn voor de reactie op chemotherapie en overlevingsduur van patiënten. Vervolg onderzoek in deze patiëntengroep liet geen duidelijke correlatie zien tussen CSC en EMT kenmerken in de tumor en het aantal CTC in het bloed van patiënten. Wel leken tumoren met verhoogde mesenchymale kenmerken samen te hangen met een betere prognose, wat enigszins verrassend is aangezien de theorie het tegenovergestelde voorspeld. Ten slotte, in een niet-kleincellig celkweekmodel bezaten mesenchymale cellen verhoogde chemoresistentie, invasief gedrag en CSC eigenschappen ten opzichte van epitheliale cellen.
Concluderend, de bijdrage van CSC en EMT bij longkanker is niet eenduidig in deze studies en dient nader uitgezocht te worden.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Kruyt, Frank, Supervisor Hiltermann, Jeroen, Co-supervisor Meijer, Coby, Co-supervisor
Datum van toekenning	16-mrt.-2016
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-90-367-8675-1
Elektronische ISBN's	978-90-367-8674-4
Status	Published - 2016

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Title and contents Final publisher's version, 107 KB
Chapter 1Final publisher's version, 178 KB
Chapter 2Final publisher's version, 789 KB
Chapter 3Final publisher's version, 1,02 MB
Chapter 4Final publisher's version, 453 KB
Chapter 5Final publisher's version, 5,88 MB
Chapter 6Final publisher's version, 1,23 MB
Chapter 7Final publisher's version, 300 KB
Chapter 8Final publisher's version, 247 KB
Chapter 9Final publisher's version, 250 KB
Complete thesisFinal publisher's version, 9,88 MB
PropositionsFinal publisher's version, 54,4 KB

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title = "Cancer stem cells and epithelial-to-mesenchymal transition in lung cancer",

abstract = "Lung cancer is a devastating disease and the number of deaths by lung cancer alone exceeds that of all other types of cancer-related deaths combined. In recent years role of Epithelial to mesenchymal transition (EMT), Circulating Tumor Cells (CTC) and Cancer Stem Cells (CSC) has been well established in metastatic spread of disease. Activation of EMT in primary tumors generates highly invasive and migratory mesenchymal cells, which could enter in blood or lymphatic circulation. These CTCs may have CSC like properties; extends to secondary sites giving rise to metastasis. In this thesis we have described a possible enrichment of CSC properties measured by SOX2 and CD44 as disease progressed from sensitive to refractory to therapy using three cell line panel previously derived from one SCLC patient. This thesis also includes a multicenteric clinical study where we showed that CTC{\textquoteright}s have prognostic and predictive value in SCLC. Further we used the biopsy material from same patients and showed that tumors with high epithelial characteristics have worse overall survival. In NSCLC A549-EMT model we demonstrated that mesenchymal cells display enhanced chemoresistance, migration potential, invasion capacity and CSC properties compared to epithelial cells. We investigated the potential of CSC enrichment of esophageal adenocarcinoma (EAC) cells in 3D spheroid cell culture and subcutaneous animal model. This thesis also discussed on current and novel methods of targeting apoptosis pathways in lung cancer as therapeutic strategies.",

author = "Pore, \{Milind M.\}",

year = "2016",

language = "English",

isbn = "978-90-367-8675-1",

publisher = "Rijksuniversiteit Groningen",

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T1 - Cancer stem cells and epithelial-to-mesenchymal transition in lung cancer

AU - Pore, Milind M.

PY - 2016

Y1 - 2016

N2 - Lung cancer is a devastating disease and the number of deaths by lung cancer alone exceeds that of all other types of cancer-related deaths combined. In recent years role of Epithelial to mesenchymal transition (EMT), Circulating Tumor Cells (CTC) and Cancer Stem Cells (CSC) has been well established in metastatic spread of disease. Activation of EMT in primary tumors generates highly invasive and migratory mesenchymal cells, which could enter in blood or lymphatic circulation. These CTCs may have CSC like properties; extends to secondary sites giving rise to metastasis. In this thesis we have described a possible enrichment of CSC properties measured by SOX2 and CD44 as disease progressed from sensitive to refractory to therapy using three cell line panel previously derived from one SCLC patient. This thesis also includes a multicenteric clinical study where we showed that CTC’s have prognostic and predictive value in SCLC. Further we used the biopsy material from same patients and showed that tumors with high epithelial characteristics have worse overall survival. In NSCLC A549-EMT model we demonstrated that mesenchymal cells display enhanced chemoresistance, migration potential, invasion capacity and CSC properties compared to epithelial cells. We investigated the potential of CSC enrichment of esophageal adenocarcinoma (EAC) cells in 3D spheroid cell culture and subcutaneous animal model. This thesis also discussed on current and novel methods of targeting apoptosis pathways in lung cancer as therapeutic strategies.

AB - Lung cancer is a devastating disease and the number of deaths by lung cancer alone exceeds that of all other types of cancer-related deaths combined. In recent years role of Epithelial to mesenchymal transition (EMT), Circulating Tumor Cells (CTC) and Cancer Stem Cells (CSC) has been well established in metastatic spread of disease. Activation of EMT in primary tumors generates highly invasive and migratory mesenchymal cells, which could enter in blood or lymphatic circulation. These CTCs may have CSC like properties; extends to secondary sites giving rise to metastasis. In this thesis we have described a possible enrichment of CSC properties measured by SOX2 and CD44 as disease progressed from sensitive to refractory to therapy using three cell line panel previously derived from one SCLC patient. This thesis also includes a multicenteric clinical study where we showed that CTC’s have prognostic and predictive value in SCLC. Further we used the biopsy material from same patients and showed that tumors with high epithelial characteristics have worse overall survival. In NSCLC A549-EMT model we demonstrated that mesenchymal cells display enhanced chemoresistance, migration potential, invasion capacity and CSC properties compared to epithelial cells. We investigated the potential of CSC enrichment of esophageal adenocarcinoma (EAC) cells in 3D spheroid cell culture and subcutaneous animal model. This thesis also discussed on current and novel methods of targeting apoptosis pathways in lung cancer as therapeutic strategies.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-8675-1

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -

Cancer stem cells and epithelial-to-mesenchymal transition in lung cancer

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