The importance of tryptophan catabolism in a wide variety of cancers is well established. Our metabolomic study revealed two EV-derived metabolites of the tryptophan pathway, reaching statistical significance based on the significance versus fold-change values (FC > 2, p ≤ 0.05) compared with controls. The prostate carcinoma cell line-derived EVs carrying tryptophan were significantly enriched (log2 (FC) = 2.8, p = 0.0007), and the colon carcinoma kynurenine was significantly decreased (log2 (FC) = -4.9, p = 0.04). Surprisingly, our results for these two metabolites were the opposite of the tryptophan and kynurenine concentrations detected in the serum or tissue samples of cancers. Accurately, tryptophan levels are commonly low and kynurenine levels are high, also detected in CRC and prostate carcinoma.318 This is in line with our study of CTCL, where plasma levels of tryptophan were significantly downregulated and kynurenine levels were upregulated.
The transport system of maintaining a high kynurenine level and a low tryptophan level in cancer cells is not fully understood.255 The drawback of our study is that only two metabolites from the kynurenine pathway reached the lower limit of quantification. However, the findings that kynurenine and tryptophan are packed into EVs will likely be important. The hypothesis that the Kyn/Trp balance regulation in cancers is EV-mediated may open a new perspective for exploring the transport mechanism further. Primarily, tryptophan was significantly enriched in cancer EVs, suggesting that the transport of tryptophan out of the cells may be EV-mediated. The opposite was true for kynurenine since kynurenine was significantly reduced in cancer EVs, supposed to maintain high kynurenine levels inside the cell. The phase III clinical trial of blocking the IDO1 with epacadostat did not reach significant improvement of melanoma patients, indicating limited
another mechanism, in addition to the IDO1, compensates the blocked IDO1 and maintains the Kyn/Trp ratio and promotes the immunosuppressive environment should be considered. Future studies should thus examine the role of EVs in IDO1/ TDO-mediated immunosuppression.
7. CONCLUSION
The findings presented in this thesis represent an essential contribution to understanding the role of TME in the pathogenesis of CTCL. Our efforts to analyze altered metabolites of the tryptophan pathway reveal the important role of IDO1 and TDO in different CTCL subtypes. In future, confirmation of the serum Kyn/Trp ratio as a biomarker of CTCL may be valuable. Furthermore, the strategy of combined IDO1/ TDO inhibition therapy may achieve superior results for CTCL treatment, as TDO acts as a compensatory enzyme for IDO1, both expressed in CTCLs.
The discovery that the human endogenous retrovirus origin syncytin-1 was overexpressed in CTCL cell lines and in cell-derived EVs may help answer the question of the evolutionary origin of EVs. Since human syncytin-1 has retained its receptor-mediated cell membrane fusion capacity, the syncytin-1-carrying EVs may facilitate cell-to-cell fusion in cancer cells and transfer tumor cell signals to recipient cells. Targeting and eradicating cancer-associated molecules exposed on the surface of cancer-EVs but absent in normal EVs, including syncytin-1, may be a valuable next-generation strategy for cancer treatment.
Our findings of metabolomic alterations in cancer-derived EVs, including CTCL, prostate carcinoma, and colon carcinoma, reflects the cancer-associated metabolic imbalance into EVs. We detected common metabolites of EVs, namely proline, succinate, folate, and creatinine, from all studies cancer types. These altered EV-transported metabolites may be useful in discovery of biomarkers and in shedding light on the complex metabolic network that is fundamental for cancer progression.
8. ACKNOWLEDGMENTS
This study was conducted at the Department of Dermatology and Allergology, University of Helsinki, and Helsinki University Hospital, Finland, during the years 2016–2021. I want to acknowledge the high-quality research facility and inspiring work environment at the Skin and Allergy hospital and Biomedicum Helsinki. I want to express my gratitude to the patients and volunteers who donated their samples to this research.
The study has been financially supported by grants from the Cancer Foundation Finland, the Finnish Dermatological Society, the Ida Montin Foundation, and the Doctoral School in Health Science. I am grateful for their support.
I am incredibly thankful to my supervisor Professor Annamari Ranki for the opportunity to conduct my doctoral thesis and for her support, mentorship, and patience during this project. Her experience, academic knowledge, positive energy, and kindness are admirable.
I thank my co-authors, collaborators, and colleagues. I am incredibly thankful to Francois Mallet for his excellent knowledge about the syncytin-1 protein.
He was always willing to answer my questions and provided valuable opinions during our project. I am grateful to the personnel of the EV core facility for their impressive knowledge and cooperation concerning extracellular vesicles. Without their help, this thesis would not be possible. Special thanks to Mari Palviainen, who guided me to the world of extracellular vesicles. It has been an excellent opportunity to work with Mari. Her inspiring, helpful, and optimistic attitude has made my journey marvelous. I appreciate your friendship! I thank Pia Siljander for the excellent collaboration. Her knowledge of extracellular vesicles is impressive. I thank Maija Puhka for the opportunity to learn so much about electron microscopy. I have spent wonderful times taking photographs from the EVs and enjoying your peaceful company. I thank Biomedicum Imaging Unit for advice and support. Special thanks to Pilvi Maliniemi for sharing your article with me. It was a pleasure to work with you!
I want to express my gratitude to all my lab members. Especially Annika, thank you for sharing your knowledge and cooperating during my projects. Alli, without you, it would be impossible to work in the lab. You take care of everything, and I am always grateful for your assistance. Thank you, Eira, for the excellent company, for example, at the faculty Christmas party! Thank you, Al Amin, for your peaceful attitude and company. Thank you Martta, Liisa, and Tea from the IAS. Tea, I want to thank you for your wonderful and inspiring attitude during our current project! Thank you, Inga, and Mirjam for your technical assistance.
It has been pleasant to work with you! Thank you, Juli, for your secretary’s help.
I appreciate your helpfulness. I want to thank previous lab members: Kaija, Dmitri, and Markus. I am also grateful to Professor emeritus Kaj Krohn for his valuable knowledge and opinions.
I want to thank my thesis committee members, Professor Tom Böhling and Docent Erja Kerkelä, for their support during my thesis. Special thanks to Professor Jyrki Heino and Docent Kirsi Rilla for reviewing my thesis. Your views have been valuable. I am profoundly grateful to Professor Veli-Matti Kähäri for being my opponent. I am also appreciative of Doctoral School in Health Science and Doctoral Programme in Interactive Life Science for excellent courses and support during my thesis. Thank you, Carol Ann Pelli, for the language editing.
My journey to this moment has been long, unusual, and marvelous. I want to express my gratitude to all inspiring and intelligent people during my career.
First of all, I want to thank Professor Helena Kääriäinen, who offered me the opportunity to work at the Department of Medical Genetics beginning of the year 1991. Since then, I wanted to study more molecular biology, and fortunately, I had wonderful opportunities to work in excellent research groups and take part in many colleagues’ PhD projects. I will never forget Professor Albert de la Chapelle and his impressive intelligence. I also have the honor of doing research with Professor Kristina Aittomäki, who greatly encouraged and inspired me. I want to especially thank Professor Lauri Aaltonen and his research group for an encouraging and wonderful working environment that inspired me to continue my studies. So many people I am grateful to, but it would take several pages to write all names here! I will never forget the Karyon Oy and its funny and lovely colleagues and I am grateful for their company and especially for the nice parties!
I want to thank Professor Iiris Hovatta for her excellent skill in supervising me in my pro graduate thesis. I had a wonderful time in your friendly and talented lab. The department of Equine and Small Animal Medicine: Merja, Kaisa and Taina, I want to thank you for the best possible friendship and support.
Rakkaimmat kiitokset perheelleni ja ystävilleni. Ilman teidän kannustavaa tukeanne väitöskirjani ei olisi valmistunut. Kiitos Elli, että sain käyttää maalaustasi kirjani kannessa. Kiitos Satu, Paula, Kiiki, Maria, Lotta, Heikki ja Tani-serkku sekä monet muut ystäväni kannustuksesta ja hauskoista yhteisistä rentoutushetkistä kiireenkin keskellä. Kiitos sielunsiskoni Taija ihanista keskusteluista sekä tuesta elämän monissa kiemuroissa. Olet esikuvani niin tieteen saralla kuin myös ihanana ihmisenä. Kiitos isä ja äiti kaikesta mahdollisesta tuesta ja välittämisestä koko elämäni aikana. Isälle vielä kiitos kiinnostuksesta biologiaa kohtaan. Samille kiitos olemalla oma itsesi sekä ”sparraavista” ajatuksistasi. Olet kyllä hyvä tyyppi!
Sara siskoni ja sielunkumppanini, eihän tästä elämästä tulisi mitään ilman sinua.
Kiitos tuntien keskusteluista sekä, että olet ollut läsnä ja tukenani koko elämäni ajan. Kiitos Emmille, kun olet jaksanut vastailla kysymyksiini ”kieliongelmissa”.
On ollut hienoa seurata opiskeluasi ja rohkeuttasi tehdä päätöksiä. Rakkaat
tottuneet siihen, että äiti opiskelee aina jotain ja suhtaudutte siihen kannustavasti ja ylpeydellä. Rakkaimmat kiitokset kaikesta! Ari, rakkauteni, kumppanini ja mentorini, olet auttanut minua selviämään tästä koitoksesta olemalla läsnä, kuuntelemalla, kannustamalla sekä ihan konkreettisesti monissa teknisissä pulmissa, kirjan taittamisessa sekä kuvien viimeistelyssä. Sanat eivät riitä osoittamaan kiitollisuuttani!
Kirsi Laukkanen Porvoo, August 2021
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