IntroductionCancer is defined by the World Health Organisation as”the uncontrolled growth and spread of malignant cells” and can virtually affectany body part. Breast cancer (BC) is the leading cause of deaths from cancer inwomen worldwide (Harbeck and Gnant,2017)and despite novel therapeutics and more personalised strategies, deaths fromthe disease amounted to more than half a million in 2015 (WHO,2017). While earlierdetection and more efficient strategies are expected to lower BC mortality in developedcountry, the increasing life expectancy in developing countries is accompaniedwith higher BC incidence as age remains a major risk factor (McGuire et al.,2015; Harbeck and Gnant,2017). However, primary breast tumour is not the cause ofdeaths in most cases as unlike other organs, the breast isn’t essential forsurvival (Kitamura and Pollard,2015). Thus, BC patients mainly die from secondarylesions, after malignant cells spread to other body parts (Kitamura andPollard,2015). Patients not diagnosed early enough can therefore present to theclinic with metastases to lymph nodes, the skin, bones, lungs or the brain,which negatively impacts the prognosis of survival (Hayat et al.
,2007). Inother cases, treatment can eradicate the primary cancer but malignant cells canremain undetected within the body in a state of dormancy before proliferatingagain months to years later (Hurst et al.,2016). Consequently, this is an important research area and myproject will explore the hypothesis that perivascular matrix proteinsfacilitate macrophage-mediated breast cancer invasion by affecting macrophages’phenotype and invasion processes.
Thus, this project preview dissertation willdescribe the known mechanisms of invasion and metastasis before discussing whyit cannot yet be prevented due to the not fully elucidated involvement of thetumour microenvironment. Roles of macrophages in cancer invasion will then beemphasised and the implication of the extracellular matrix outlined. Finally,the importance of this project and areas requiring further research will bediscussed.I) Metastasis:The Challenge of Breast CancerWhile metastasis is thought to be the cause of 90% ofcancer-related deaths, its mechanisms in cancer pathogenesis remain unclear (Lambert, Pattabiraman and Weinberg,2017). It thereforerepresents a crucial target in the fight against cancer.
A) TheInvasion-Metastasis Cascade In order for malignant cells to spread from theprimary tumour to the lymphatic or blood vasculature and then to distantorgans, they must acquire migratory and invasive properties (Figure 1)(Chaffer and Weinberg,2011). This complexmultistage process, the so-called invasion-metastasis cascade, relies on amyriad of signals, currently investigated for potential anti-metastatic strategies(Kitamura and Pollard,2015). Factors, including tumour growth factor-Beta(TGF-?) and Wnt, enable cancerous cells to undergo an epithelial-to-mesenchymaltransition (EMT), giving them an invasive phenotype (Kitamura and Pollard,2015).
Consequently, the inhibition of TGF-? receptor prevents EMT and invasion inmammary carcinomas models in vivo, highlighting its key role (Oft, Heider and Beug,1998). Thus, EMT ischaracterised by the shift from epithelial-specific E-cadherins to N-cadherins’expression, allowing cancerous cells to lose cell-cell and cell-ECM contact (Lamouille, Xu and Derynck,2014). Additionally,EMT permits cells to survive anoikis, a programmed cell death normally causedby detachment from the ECM (Lamouille, Xu andDerynck,2014). Finally, this phenotypic shift allows cells to degradethe ECM of surrounding tissue by secreting matrix metalloproteinases (MMP) andto move towards lymphatic and blood vessels, where they intravasate afterdegrading their basement membrane (Lamouille, Xuand Derynck,2014). This initial migration towards blood vessels istherefore crucial for a ductal carcinoma in situ (DCIS) to degenerate into aninvasive ductal carcinoma (IDC) and its prevention could limit the mortalityassociated with BC.
Thus, findings that macrophages and specific ECM proteinsare overrepresented in tumour stroma will underlie my upcoming investigationson their hypothesised implication in BC invasion (Acerbi et al.,2015).