Wnt Signalling and Cancer Outline
Wnt Signalling and Cancer
Definition of Wnt signalling
Thesis statement: The paper analyses the role of Wnt pathways in the development of breast and ovarian cancer in order to understand how Wnt regulation may contribute to cancer therapy.
Types of Wnt pathways: Canonical and non-canonical pathways
Wnt antagonists: SFRP4
Stem cell and stem cell-like cells
Role of Wnt in the development of breast cancer
Role of Wnt in the development of ovarian cancer
Wnt Signalling and Cancer
Wnt signalling pathways arehighly significant protein substances within the body. They areresponsible for passing signals across cell membrane receptors fromwithout the cell to within the cell. This communication can occureither among neighbouring cells or within the same cell. The pathwaysplay a regulatory role in that it regulates gene transcription,cytoskeleton, and calcium within the cell. Wnt signalling pathwaysare unique in that they are similar in several species. The pathwaysare also associated with embryonic development and carcinogenesis.They regulate processes such as cell migration, proliferation, andcell fate specification. When wnt signalling is activated aberrantly,it leads to poor prognosis of various cancers such as ovarian andbreast cancer. The pathways may also lead to cancer formation due tode-regulation. This paper analyses the role of wnt signalling in thedevelopment of breast and ovarian cancer in order to understand howwnt regulation may contribute to cancer therapy.
There are three main types of Wntpathways. These include canonical, non-canonical pathways dependingon their dependence on beta catenin. Canonical pathways depend onbeta catenin while non-canonical pathways do not. Research shows thatWnt antagonists are often deactivated in cancer patients. SecretedFrizzled Receptor Proteins (SFRP 1-5) are good examples of the Wntantagonists. SFRP 4 deactivation is especially associated withdevelopment of ovarian and breast cancer since it is often depositedinto the blood stream giving room for the action of Wnt proteins.Patients who lack SFRP4 express faster cancer progression because oflack of proper wnt regulation.
Stem cell and stem-like cells areassociated with the development of breast cancer. Breast cancer cellsthat contain the CD44+CD24-/low surface markers are tumourigenic andmay thus lead to the spread of tumours. Wnt1 expression increases theproliferation of stem cells, enhances senesce failure, and increasesresistance to apoptosis. The regulation of progenitor and stem cellsby wnt signalling is also responsible for the resistance ofanti-cancer therapies.
Role of Wnt in the Developmentof Breast Cancer
Lamb et al. (2013) conducted astudy using normal and metastatic human breast cancer cells todetermine the role of Wnt in breast cancer development. The cellswere collected from human participants’ tissues. Several studieswere then conducted including Wnt inhabitation and activation,microassay analysis, breast cancer microarray, and RNA extraction ofthe breast cells. mRNA expression in breast cells show that geneexpression is specific along specific lines. For instance, somedownstream targets like LEF1 and AXIN2 manifest higher expression,and this indicates canonical wnt signalling activation. The resultsof the study confirm the presence of wnt signalling in metastaticbreast cells while its activation is minimal in normal breast cells.Further, the study helped determine the role of wnt expression inbreast cancer. Here, low expression of SFRP1and LEF1 leads toincreased chances of cancer recurrence as it indicates Wnt signallinginhibition. On the other hand, high expressions indicate a risk ofearly recurrence. This was discovered after analysing wnt5b.
The activation of Wnts pathwaywas determined using stem-like breast cancer cells. This wasascertained by the increase in AXIN2, LEF1, DKKInand bata-cateninexpression in anoikis resistant cells during the mammosphere culture.In addition, the study confirmed that normal stem-like breast cellsdo not undergo wnt signalling due to suppression. A comparative studyshowed that breast cancer cells express more Wnt signalling thannormal cells do. It was also observed that Wnt ligands were expressedbetter in AR cells as compared to monolayer cells for the normalcells. However, the reverse was true for the cancer cells. The studywas also significant in determining the role of Wnt pathwaysignalling modulation on stem-like cell action. In cases where Wntpathways are inhibited, mammosphere formation occurs at low doses oftreatment in cancer cells while none occurs in the normal cells.
Role of Wnt in the Developmentof Ovarian Cancer
Wnt signalling has also beenassociated with ovarian cancer. Ovarian cancer affects the epithelialcells of ovaries in women. The development of ovarian cancer isassociated with the deregulation of wnt signalling which leads tometastasis and tumourigenesis. Development of this cancer is moreprogressive in patients without SFPR4 due to the inefficient wntregulation. The cancer cells also enhance their invasive activity byhijacking the Epithelial to Mesenchymal Transition (EMT) process. Theprocess plays a significant role in metastatis and organogenesis whenit occurs in reverse, that is, Mesenchymal to Epithelial Transition(MET). Wnt regulation can therefore play an important role indetermining the most effective cancer therapy.
Ford et al. (2013) conducted aresearch to determine the effect of regulating Wnt pathways in thecure of ovarian cancer. The study involve experimentation using humanserous ovarian cancer cells in 10% fetal calf serum, streptomycin,penicillin, and GlutaMAX in controlled environment to determineabsence of mycoplasma contamination. The cells were then used toconduct a Wnt reporter assay followed by a quantitative reversetranscriptase PCR. Western blots were also conducted using cell andnucleus lyses and antibodies against SFRP4, E-cadherin, Vimentin,twist, B-Catenin, Histone H3, and alpha-Tubulin. Migration assayswere also conducted using the ovarian cancer cells on IBIDIculture-inserts. Finally, adhesion assays were performed on theculture.
According to this research,recombinant SFRP4 extracted from human cells may offer a solution tothe treatment of ovarian cancer. The study proposes that the loss ofSFRP4 in epithelial ovarian cancer can be addressed thorough theintroduction of rSFRP4 to inhibit canonical Wnt signalling. CanonicalWnt is B-Catenin dependent and thus its inhibition leads to theinhibition of B-Catenin. The human serous ovarian cancer cells aresuitable for this study because they do not express any SFRP4 andthey contain a lot of B-Catenin. Through the Wnt reporter assay, itwas determined that the ovarian cancer cells were responsive to Wntthrough the increase of Beta Catenin levels following rWnt3astimulation. Further, the rSFRP4 was added serially to determine thelevels at which all the B-catenin would be inhibited. According tothis study, this level was at 5 ug/ml. It was also evident that bothB-catenin and Wnt signalling reduced with increasing amounts ofrSFRP4. However, the addition of rSFRP4 did not lead to reductions inWnt signalling (Ford et al. 2013).
Further, the serial addition ofrSFRP4 to the ovarian cancer cells also helped determine the effectof SFRP4 on cancer cells adhesion and migration. According to Ford etal. (2013) SFRP4 reduces the rate of cancer cells migration. Thishelps prevent the spread of the cancer cells significantly. SFRP4regulator also helps the ovarian cancer cells to attach themselves tocollagen and fibronectin. This is significant because it is able toinhibit metastasis thus reducing the rate of cancer development andthis in turn increases one’s survival chances. SFRP4 was also foundto inhibit EMT in the ovarian cancer cells through this study.
In brief, Wnt pathways play acrucial role in the development of ovarian and breast cancer. Studiesoffer credible evidence regarding the role of Wnt in cancer. Forinstance, Lamba et al (2013) establish the role of wnt signallingactivation in determining the rate of cancer recurrence. Wntexpression plays a prognostic role in breast cancer according to Lambet al. (2013). Moreover, the study establishes that wnt pathwayactivation results in faster progression of tumours in cancer cellsdue to increased beta catenin expression. According to Ford et al.(2013), wnt signalling is also responsible for the development ofovarian cancer. The study determines that wnt regulators areinhibited in cancer cells leading to faster cancer progression due toenhanced cancer cell migration. Such regulators include SFRP 1-5.Introducing these regulators in the cell leads to lower cancerprogression due to the ability to moderate wnt and reduce betacatenin production.
The studies analysed hereinindicate that Wnt regulation is impared in cancer cells. This impliesthat resistance to current cancer therapies is associated with thisanomaly. Lack of Wnt regulation also leads to increases in betacatenin, which leads to enhanced migration of cancer cells. However,the studies do not offer the way forward for cancer treatmentoptions. There is need to use these findings to create recombinantWnt antagonists such as SFRP4 in order to reduce cancer progression,reduce migration of cancer cells, and enhance adherence of cancercells. There is also need for an in-depth study of Wnt ligands toenhance specificity between the ligands and the wnt antagonists.
Ford CE, Jary E, Ma SSQ, NixdorfS, and Heinzelmann-Schwarz VA. 2013. “The Wnt Gatekeeper SFRP4Modulates EMT, Cell Migration and Downstream Wnt Signalling in SerousOvarian Cancer Cells.” PLoSONE 8(1): e54362.doi:10.1371/journal.pone.0054362
Lamb R, Ablett MP, Spence K,Landberg G, and Sims AH. 2013. “Wnt Pathway Activity in BreastCancer Sub-Types and Stem-Like Cells”. PLoSONE 8(7): e67811.doi:10.1371/journal.pone.0067811