26 september 2018: Bron: Pubmed

Ik heb eens in pubmed gezocht op het eiwit WNT16B naar aanleiding van het artikel hieronder en kom op interessante studies.

Met als kernboodschap dat het eiwit WNT16B een rol speelt in het resistent worden tegen chemotherapie en waarschijnlijk ook hormoontherapie. Lees daarvoor ook het originele artikel uit 2012 verderop in dit artikel.

Klik op de titels van de publicaties om de studierapporten te lezen.

In willekeurige volgorde, abstracten staan onderaan artikel.

Dit studierapport: 

Treatment-induced secretion of WNT16B promotes tumor growth and acquired resistance to chemotherapy  

is gratis te lezen. Het abstract staat onderaan dit artikel.

Citaat uit het abstract:

In een recent artikel in Nature Medicine, Sun et al. toont aan dat verhoogde expressie van een eiwit uit de Wnt familie (WNT16B)' als reactie op cytotoxische schade tumorgroei en resistentie tegen chemo kan bevorderen. Zulke bevindingen schetsen een mechanisme waarmee cytotoxische therapieën die in cyclische doses worden gegeven, de ressitentie van de behandeling in feite kunnen vergroten en mogelijk de deur openen naar nieuwe onderzoeksgebieden en naar de ontwikkeling van nieuwe therapeutische doelen die het DNA-schade-responsprogramma blokkeren. 

Ook deze studie ziet het effect dat het eiwit WNT16B heeft bij optredende resistentie tegen chemo, al zien de odnerzoekers ook hoe een ander stofje dit zou kunnen opheffen 

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment.

(We found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. )

Vertaling met google translate: 

We vonden dat WNT16B een centrale rol speelt bij het bevorderen van gevorderde maligniteiten, met name verworven resistentie door het tegengaan van celdood, een effect dat kan worden geminimaliseerd door een neutraliserend antilichaam dat gelijktijdig wordt toegediend met klassieke chemotherapie. Bovendien is de door DNA-schade teweeggebrachte expressie van WNT16B systemisch, afgebeeld door significante inductie tussen diverse vaste organen en circulatie in perifeer bloed, waardoor het veelbelovend is als niet alleen een van TME afgeleid antikankerdoel, maar ook een nieuwe biomarker voor klinische evaluatie van de werkzaamheid van de behandeling.

Hier 1 grafiek uit verschillende grafieken die in bovenstaande studie zijn vermeld.

Zie het grote verschil in kolom G tussen behandelde en niet behandelde patienten in de expressie van het eiwit WNT16B in onderstaande afbeelding. 

PMC full text:

Figure 2

An external file that holds a picture, illustration, etc. Object name is onc2015494f2.jpg

SFRP2 is differentially expressed between stromal and epithelial cells in response to DNA damage. (a) Measurement of SFRP2 transcription in prostate fibroblasts and epithelial cells after genotoxic treatments (MIT, SAT and RAD), data normalized to untreated controls per line. (b) Protein-level examination with samples collected from cell lines used in a. IC and CM samples of each line were collected ~10 days after γ-irradiation treatment, GAPDH as a loading control. (c) Expression profiling of SFRP2 in distinct cell subpopulations separately isolated by laser capture microdissection from OCT-embedded tissue specimens of human CRC patients who either received direct surgery or underwent neoadjuvant chemotherapy before surgery. Data normalized to the lowest ΔCT in the pre-treatment group. Pre-, Pre-chemotherapy; Post-, Post-chemotherapy. Each data point represents an individual patient; n=10. (d) Representative HE and IHC staining images of sequential sections from human CRC patient specimens analyzed in c. Left column, HE staining; central and right columns, IHC staining. Anti-SFRP2 and anti-WNT16B were applied to tissues to probe the expression of designated antigens, respectively. Scale bar, 150 μm. Black arrows, stroma. (e) Pathological assessment of SFRP2 stromal expression in CRC patient tissues. For either pre- or post-treatment group, n=40. Patients were assigned to four categories per IHC staining intensity. 0, no expression; 1, faint expression; 2, moderate expression; 3, strong expression. P<0.01 by ANOVA. (f) IHC evaluation of WNT16B stromal expression in the same CRC patient cohort. (g) Co-expression of SFRP2 and WNT16B in stroma, corresponding R2 represents a best fit linear regression with Pearson correlation analysis.

Een andere studie is deze: 

WNT16B from ovarian fibroblasts induces differentiation of regulatory T cells through β-catenin signal in dendritic cells.

Het studierapport is volledig gratis te lezen. Hier het summiere abstract:

Treatment for cancer can induce a series of secreted factors into the tumor microenvironment, which can affect cancer progression. Wingless-type MMTV (mouse mammary tumor virus) integration site 16B (WNT16B) is a new member of the WNT family and has been reported to play growth-related roles in previous studies. In this study, we found WNT16B could be expressed and secreted into the microenvironment by human ovarian fibroblasts after DNA damage-associated treatment, including chemotherapy drugs and radiation. We also demonstrated that fibroblast-derived WNT16B could result in accumulation of β-catenin in dendritic cells and secretion of interleukin-10 (IL-10) and transforming growth factor beta (TGF-β), which contributed to the differentiation of regulatory T cells in a co-culture environment. These results shed light on the roles of WNT16B in immune regulation, especially in regard to cancer treatment.

Innate or acquired resistance to chemotherapy presents an important and predictable challenge in cancer therapy. Malignant tumors consist of both neoplastic and benign cells such as stromal fibroblasts, which can influence the tumor’s response to cytotoxic therapy. In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. Such findings outline a mechanism by which cytotoxic therapies given in cyclical doses can actually augment later treatment resistance and may open the door to new areas of research and to the development of new therapeutic targets that block the DNA damage response program.

Although further studies are necessary to develop agents that block the DNA damage response program or chemotherapeutic agents that do not trigger it, the findings of Sun et al. provide considerable insight into the roots of chemotherapy resistance that may be used to guide future drug development.

. 2013 Feb 1; 14(2): 90–91.
PMCID: PMC3572004
PMID: 23114711

Treatment-induced secretion of WNT16B promotes tumor growth and acquired resistance to chemotherapy

Implications for potential use of inhibitors in cancer treatment
Linda M. Johnson, 1 Douglas K. Price, 1 and William D. Figg 1 , 2 ,*
Author information ► Copyright and License information ► Disclaimer

Abstract

Innate or acquired resistance to chemotherapy presents an important and predictable challenge in cancer therapy. Malignant tumors consist of both neoplastic and benign cells such as stromal fibroblasts, which can influence the tumor’s response to cytotoxic therapy. In a recent article in Nature Medicine, Sun et al. show that increased expression of Wnt family member wingless-type MMTV integration site family member 16B (WNT16B) by the tumor microenvironment in response to cytotoxic damage and signals through the canonical Wnt pathway to promote tumor growth and chemotherapy resistance. Such findings outline a mechanism by which cytotoxic therapies given in cyclical doses can actually augment later treatment resistance and may open the door to new areas of research and to the development of new therapeutic targets that block the DNA damage response program.

References

1. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92. doi: 10.1002/path.1706. [PubMed] [Cross Ref]
2. Kerbel RS, Kobayashi H, Graham CH. Intrinsic or acquired drug resistance and metastasis: are they linked phenotypes? J Cell Biochem. 1994;56:37–47. doi: 10.1002/jcb.240560108. [PubMed] [Cross Ref]
3. Davis AJ, Tannock JF. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol. 2000;1:86–93. doi: 10.1016/S1470-2045(00)00019-X. [PubMed] [Cross Ref]
4. Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012 doi: 10.1038/nm2890. [PMC free article] [PubMed] [Cross Ref]
5. Binet R, Ythier D, Robles AI, Collado M, Larrieu D, Fonti C, et al. WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway. Cancer Res. 2009;69:9183–91. doi: 10.1158/0008-5472.CAN-09-1016. [PubMed] [Cross Ref]
6. Fear MW, Kelsell DP, Spurr NK, Barnes MR. Wnt-16a, a novel Wnt-16 isoform, which shows differential expression in adult human tissues. Biochem Biophys Res Commun. 2000;278:814–20. doi: 10.1006/bbrc.2000.3852. [PubMed] [Cross Ref]
Articles from Cancer Biology & Therapy are provided here courtesy of Taylor & Francis

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment

. 2016 Aug 18; 35(33): 4321–4334.
Published online 2016 Jan 11. doi:  10.1038/onc.2015.494
PMCID: PMC4994019
PMID: 26751775

SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment

Y Sun,1,2,3,* D Zhu,4 F Chen,1 M Qian,1 H Wei,5 W Chen,5 and J Xu4
Author information ► Article notes ► Copyright and License information ► Disclaimer

Abstract

Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-κB (NF-κB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments β-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co-administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine.

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Noncancerous fibroblasts when exposed to chemotherapy sustain DNA damage that drives the production of an array of factors that stimulate solid tumor cancer growth

Cancer chemotherapy resistance: Hutchinson Center team discovers new mechanism

Noncancerous fibroblasts when exposed to chemotherapy sustain DNA damage that drives the production of an array of factors that stimulate solid tumor cancer growth

Aug 6, 2012
By Kristen Woodward
Dr. Peter Nelson

Dr. Peter Nelson of the Human Biology Division

Photo by Dean Forbes

Developing resistance to chemotherapy is a nearly universal, ultimately lethal consequence for cancer patients with solid tumors – such as those of the breast, prostate, lung and colon – that have metastasized throughout the body. A team of scientists led by the Hutchinson Center has discovered a key factor that drives this drug resistance – information that ultimately may be used to improve the effectiveness of therapy and buy precious time for patients with advanced cancer.

"Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy," said senior author Dr. Peter Nelson, of the Hutchinson Center’s Human Biology Division. The findings were published online Aug. 5 in advance of print publication in Nature Medicine.

Collaborators at the Center

Co-authors included first author Dr. Yu Sun, staff scientist in the Nelson Lab; Drs. Peggy Porter of Human Biology; Ilsa Coleman of the Nelson Lab; and Dr. Tia Higano of the Clinical Research Division and University of Washington. Porter, Dr. Nicole Urban of the Public Health Sciences Division, and Dr. Beverly Torok-Storb of Clinical Research provided tissue samples for the study.

Nelson and colleagues found that a type of normal, noncancerous cell that lives in cancer’s neighborhood – the fibroblast – when exposed to chemotherapy sustains DNA damage that drives the production of a broad spectrum of growth factors that stimulate cancer growth. Under normal circumstances, fibroblasts help maintain the structural integrity of connective tissue, and they play a critical role in wound healing and collagen production.

Specifically, the researchers found that DNA-damaging cancer treatment coaxes fibroblasts to crank out a protein called WNT16B within the tumor neighborhood, or microenvironment, and that high levels of this protein enable cancer cells to grow, invade surrounding tissue and resist chemotherapy.

'Completely unexpected' increased WNT production

The researchers observed up to 30-fold increases in WNT production – a finding that was "completely unexpected," Nelson said. The WNT family of genes and proteins plays an important role in normal development and also in the development of some cancers but, until now, was not known to play a significant role in treatment resistance.

This discovery suggests that finding a way to block this treatment response in the tumor microenvironment may improve the effectiveness of therapy.

"Cancer therapies are increasingly evolving to be very specific, targeting key molecular engines that drive the cancer rather than more generic vulnerabilities, such as damaging DNA. Our findings indicate that the tumor microenvironment also can influence the success or failure of these more precise therapies." In other words, the same cancer cell, when exposed to different "neighborhoods," may have very different responses to treatment.

The major clinical reason that chemotherapy ultimately fails in the face of advanced cancer, Nelson said, is because the doses necessary to thoroughly wipe out the cancer would also be lethal to the patient.

"In the laboratory we can 'cure' most any cancer simply by giving very high doses of toxic therapies to cancer cells in a petri dish. However, in people, these high doses would not only kill the cancer cells but also normal cells and the host," he said.

Therefore, treatments for common solid tumors are given in smaller doses and in cycles, or intervals, to allow the normal cells to recover. This approach may not eradicate all of the tumor cells, and those that survive can evolve to become resistant to subsequent rounds of anti-cancer therapy.

For the study the team of researchers – which also involved investigators at the University of Washington, Oregon Health and Science University, the Buck Institute for Research on Aging, the Lawrence Berkeley National Laboratory – examined cancer cells from prostate, breast and ovarian cancer patients who had been treated with chemotherapy.

Research investment paying off

"This study is an example of collaborative, translational research that capitalizes on years of federally funded investments into the development of tissue banks and clinical trials in which we were able to track long-term patient outcomes. Investing in this type of infrastructure is critical but may take many years to see payoff," said Nelson, who serves as principal investigator of the Pacific Northwest Prostate Cancer SPORE, a federally funded, multi-institution research consortium led by the Hutchinson Center.

The National Institutes of Health, the National Cancer Institute, the Department of Defense and the Prostate Cancer Foundation funded the research.

uitzaaiïngen, metastasen, chemo, WNT16B


Plaats een reactie ...

3 Reacties op "Chemo stimuleert juist kankergroei en uitzaaiïngen door verhoogde productie van het eiwit WNT16B dat ook grote rol speelt bij wondheeling"

  • t(heo).a.muller :
    05/11/2012
    Wat velen al wisten staat hier zwart op wit en is gelukkig afkomstig uit reguliere hoek.
    Tot nu toe was alles wat regulier is het daar volstrekt miet mee eens, helaas en met ontelbare extra doden en gigantisch lijden tot gevolg.
    Hoe lang zou het duren voordat die zinloze maar vaak uiterst kostbare behandeling vervangen wordt door wel degelijk werkzame niet-reguliere behandelingen?
    Dat duurt eeuwig naar ik vrees zolang niet werkelijk democratische regeringen maar Big Pharma, Big Food en alles waar Big voor staat via lobbyisten in dient van genoemde bedrijfstakken in werkelijkheid de dienst uitmaken.
    Misschien wel het ergste is dat de onwetende burger door het kopen van de producten van die bedrijfstakken uit eigen beurs meebetalen aan hun eigen ondergang door, in dit geval een bijna verplicht gestelde behandeling met chemo toe te staan of draaf ik al teveel door?
    Zelf gezegend met een uitgezaaid melanoom ga ik dan toch maar liever gewoon dood na alle mogelijke, veelal natuurlijke mogelijkheden uitgeprobeerd te hebben en met succes tot voor kort.

    doordrammer@xs4all.nl
    Comment
    • ronald :
      01/01/2013
      Theo je spreekt jezelf tegen.
      Theo> "Hoe lang zou het duren voordat die zinloze maar vaak uiterst kostbare behandeling vervangen wordt door wel degelijk werkzame niet-reguliere behandelingen?".
      Even later zeg je > "Zelf gezegend met een uitgezaaid melanoom ga ik dan toch maar liever gewoon dood na alle mogelijke, veelal natuurlijke mogelijkheden uitgeprobeerd te hebben en met succes tot voor kort.".

      Dus GEEN succes.

      Daarbij moet je de onderzoeks gegevens niet zo zwart wit zien.
      Zowel chemo als bestraling zijn behandelmethode die niet zomaar toegepast worden, bij een dosis hoog genoeg bestaat er een verhoogde kans op de ontwikkeling van tumor vorming.
      Dit weet de oncoloog ook , hij/zij zal dan ook een afweging maken.
      Een onbehandelde uitgezaaide kanker is meestal dodelijk, een chemokuur kan hier toch nog het verschil maken.
      De afweging is dan een onvermijdelijk einde, of een behandeling die toch nog perspectief bied maar dan wel met het risico om toch nog in een later stadium een terugkerende kanker te krijgen.
      Je kunt natuurlijk je heil zoeken in het alternatieve c.q Niet reguliere circuit.
      Niet regulier betekend per definitie Niet werkzaam!
      Anders zou die behandeling wel regulier gegeven worden.
      IK wens je veel sterkte toe, en de beste wensen voor 2013!
      Comment
      • Kees :
        01/01/2013
        Ronald ik ken Theo al vele jaren. Hij heeft wel degelijk succes gehad met zijn niet-toxische aanpak (sommigen noemen dit ook alternatief). Zijn in de lymfklieren uitgezaaide melanoom is tot stilstand gekomen en hij is al 6 jaar stabiel zonder welke chemo of "reguliere" ingreep dan ook. Jij gebruikt de woorden regulier en "alternatief". Maar ook in de reguliere oncologie wordt veelvuldig gebruik gemaakt van nog niet door fase III studies bewezen middelen en behandelingen / apparaten. Want dat is de norm om opgenomen te worden in de richtlijnen. Bewijs uit liefst placebo gecontroleerde gerandomiseerde studies. Als je die criteria aanlegt voor de tot nu toe gebruikte chemo's dan voldoet bijna geen enkele chemo hieraan. En specifiek voor melanomen om maar bij Theo zijn vorm van kanker te blijven: lees dit eens: http://www.kanker-actueel.nl/NL/immuuntherapie-met-zelfgekweekte-en-daarna-ingebrachte-witte-bloedlichaampjes-zorgt-voor-spectaculaire-en-hoopvolle-genezingen-bij-melanoompatienten.html Inmiddels zijn 3 van de 5 patienten "genezen" van hun melanoom uit de fase I studie van dr. Haenen in het AvL.

        En lees dit maar: http://www.kanker-actueel.nl/NL/acute-promyelocitische-leukemie-apl-volledig-te-genezen-met-niet-toxische-aanpak-van-all-trans-retinoic-acid-atra-en-arseentrioxide-ato-en-zonder-chemo.html zonder welke chemo dan ook genezen leukemiepatienten voor 98,5 %. Opmnerkelijk aan deze studie is dat de aanpak de kannkercellen weer transformeert in gewone gezonde cellen.

        Ook jij een mooi nieuwjaar Ronald
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