Helpt u ons aan 500 donateurs?

Lees o.a. ook deze recent gepubliceerde artikelen: 

https://kanker-actueel.nl/selenium-speelt-wellicht-een-rol-in-uitzaaiingsproces-bij-prostaatkanker-blijkt-uit-onderzoek-aan-universiteit-van-wageningen.html

en: 

https://kanker-actueel.nl/groene-thee-extract-epigallocatechin-gallate-egcg-werkt-uitstekend-als-preventie-van-beginnende-kanker-door-werking-op-de-kankerstamcellen-en-rna-mutaties-en-stimuleert-effectiviteit-van-andere-medicijnen.html

maar vooral ook raadpleeg onze literatuurlijsten

26 februari 2018, Bron: Cell: DOI: doi.org/10.1016/j.cell.2016.11.037

Klik op de titel van het artikel voor het studierapport.

Uitzaaiingen van kanker zijn verantwoordelijk voor het grootste aantal aan kanker gerelateerde sterfgevallen, maar dit complexe proces van hoe ontstaan uitzaaiingen en hoe die te behandelen blijft tot nu toe het minst begrepen aspect van de kankerbiologie. Echter naarmate het wetenschappelijke onderzoek met betrekking tot uitgezaaide kanker en het uitzaaiingenproces / mechanisme zich in een snel tempo blijft ontwikkelen, worden ook de biologische principes (DNA en RNA mutaties) die ten grondslag liggen aan de verspreiding en karakter van de uitgezaaide kankercellen steeds duidelijker.

Zo wordt nog altijd aangenomen dat uitzaaiingen pas ontstaan als er al een primaire tumor is maar uit recent onderzoek bij bv alvleesklierkanker ( Rhim et al., 2012 ) zouden de uitzaaiingen al eens eerder of tegeljikertijd kunnen zijn ontstaan dan de ontdekte primaire tumor.

In een reviewstudie: Emerging Biological Principles of Metastasis worden de zogeheten cellulaire en moleculaire mechanismen samen die betrokken zijn bij het mechanisme van ontstaan van metastasen / uitzaaiingen besproken, met een focus op die vormen van kanker waar het meest van bekend is. De onderzoekers belichten de algemene principes van het ontstaan van uitzaaiingen / metastase en is m.i. bijzonder interessant voor artsen en wetenschappers. (zie verderop in dit artikel de belangrijkste conclusies uit deze reviewstudie). Hier een schematische weergave hoe uitzaaiingen meestal ontstaan:

uitzaaiingen mechanisme(2)

Figure 1

Dissemination of Carcinoma Cells

(A) Carcinoma cell dissemination occurs via two mechanisms: single-cell dissemination through an EMT (gray arrow) or the collective dissemination of tumor clusters (black arrow). Recent evidence suggests that the leader cells of tumor clusters also undergo certain phenotypic changes associated with the EMT.

(B) The epithelial state can be portrayed as the default state of residence; as cells undergo an EMT they enter into a succession of multiple epigenetic states, depicted here as free energy wells, with each state moving toward a more mesenchymal phenotype representing a higher energy state.

(C) However, the barriers between states, depicted here again as free energy wells, may be relatively low, resulting in substantial spontaneous interconversion between them, this being manifested as phenotypic plasticity.

In deze reviewstudie: Emerging Biological Principles of Metastasis wordt gedetailleerd uitgelegd hoe uitzaaiingen ontstaan en in een aantal gevallen ook hoe die te voorkomen zijn c.q. te behandelen.

Hier de belangrijkste conclusies van de studie met uitgebreide referentielijst:

We believe that an accurate comparison of the principles that govern primary tumor growth with those that govern the dissemination and outgrowth of metastases will be essential in order to enable the development of new approaches and therapies that are specifically designed to prevent or treat metastatic disease.

Review

Emerging Biological Principles of Metastasis

Arthur W. Lambert

,

Diwakar R. Pattabiraman

, Robert A. Weinberg'Correspondence information about the author Robert A. Weinberg

Conclusion: Principles and Outlook

As the preceding discussions have indicated, significant progress has been made over the past decade in elucidating the cellular and molecular programs that drive cancer metastasis. Although our understanding of metastasis remains quite incomplete, we see a number of common biological principles beginning to emerge. Thus, we suggest that one can take stock of the information that is currently at hand and conclude that:

  • 1.

    Metastasis occurs mainly through a sequential, multi-step process that can be conceptualized as the invasion-metastasis cascade.

  • 2.

    In the case of carcinomas, the EMT program enables primary tumor cells to accomplish most if not all of the steps involved in the physical dissemination of tumor cells to a distant site.

  • 3.

    The fate of disseminating carcinoma cells is strongly influenced by interactions that they experience during transit through the circulatory system.

  • 4.

    Disseminated carcinoma cells must escape clearance by the arms of the immune system and subvert the cellular programs that impose a state of dormancy.

  • 5.

    The process of active metastatic colonization is contingent upon the dissemination of cancer stem cells that can re-initiate tumor growth; the ability of their progeny to assemble adaptive, organ-specific colonization programs; and the establishment of a microenvironment conducive to metastasis.

The processes that enable the physical translocation of cancer cells from primary tumors to the parenchyma of distant tissues are within sight and relatively small in number; in contrast, the adaptive programs allowing cancer cells arising from diverse primary tumors to thrive in various tissue microenvironments may be large in number and not readily reducible to a common set of underlying mechanistic principles.

While these principles articulate general concepts, a number of key mechanistic details related to these ideas remain to be established. For example, we are beginning to appreciate that the EMT program is capable of generating a wide spectrum of carcinoma cells with various complements of mesenchymal traits, but there is little information on the functional role of these different phenotypic states in the metastatic process. Yet other critical questions about metastasis fall outside the bounds of the points outlined above. For one, it is not yet clear what specific factors determine the efficiency of clinical metastatic disease and why some patients present with metastatic cancer, while in other patients many years may lapse before the disease advances to this stage. The literature holds some provocative hints that could account for this variability (Figure 5), such as different cells of origin whose differentiation programs strongly predispose to an aggressive malignancy or to the dissemination of CTC clusters that may more readily establish a metastatic colony. Additionally, the fact that many patients experience metastatic spread to multiple organs suggests the existence of more universal, multi-organ metastatic programs, but the extent to which such programs operate is unclear and their biological details have just begun to be described. Finally, the clinical and biological impact of various immunotherapies, particularly checkpoint inhibitors (Sharma and Allison, 2015), on metastases is certain to be a continued area of active research, even offering the hope of seeking out and eliminating metastatic deposits.

Perhaps most pressing is a better understanding of the biological similarities and differences between primary tumors and their metastatic descendants, especially in regard to the extent of heterogeneity, plasticity, and resistance that they exhibit. We believe that an accurate comparison of the principles that govern primary tumor growth with those that govern the dissemination and outgrowth of metastases will be essential in order to enable the development of new approaches and therapies that are specifically designed to prevent or treat metastatic disease.

Acknowledgments

We would like to thank all members of the R.A.W. laboratory for fruitful discussions and especially Tsukasa Shibue for critical review of the manuscript. We would also like to thank Meredith Leffler for preparation of the figures. A.W.L. is supported by an American Cancer Society – New England Division – Ellison Foundation Postdoctoral Fellowship ( PF-15-131-01-CSM ). D.R.P. was supported by a C.J. Martin Overseas Biomedical Fellowship from the National Health and Medical Research Council of Australia ( NHMRC APP1071853 ) and is currently supported by a K99/R00 Pathway to Independence Award (NIH/NCI 1K99CA201574-01A1 ). Work in the R.A.W. laboratory is supported by grants from the NIH ( R01-CA078461 ), the Breast Cancer Research Foundation, the Advanced Medical Research Foundation, and the Ludwig Center for Molecular Oncology. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.


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