Introduction can virtually affect any body part.

Introduction

Cancer is defined by the World Health Organisation as
“the uncontrolled growth and spread of malignant cells” and can virtually affect
any body part. Breast cancer (BC) is the leading cause of deaths from cancer in
women worldwide (Harbeck and Gnant,2017)
and despite novel therapeutics and more personalised strategies, deaths from
the disease amounted to more than half a million in 2015 (WHO,2017). While earlier
detection and more efficient strategies are expected to lower BC mortality in developed
country, the increasing life expectancy in developing countries is accompanied
with higher BC incidence as age remains a major risk factor (McGuire et al.,2015; Harbeck and Gnant,2017).

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However, primary breast tumour is not the cause of
deaths in most cases as unlike other organs, the breast isn’t essential for
survival (Kitamura and Pollard,2015). Thus, BC patients mainly die from secondary
lesions, after malignant cells spread to other body parts (Kitamura and
Pollard,2015). Patients not diagnosed early enough can therefore present to the
clinic with metastases to lymph nodes, the skin, bones, lungs or the brain,
which negatively impacts the prognosis of survival (Hayat et al.,2007). In
other cases, treatment can eradicate the primary cancer but malignant cells can
remain undetected within the body in a state of dormancy before proliferating
again months to years later (Hurst et al.,2016).

Consequently, this is an important research area and my
project will explore the hypothesis that perivascular matrix proteins
facilitate macrophage-mediated breast cancer invasion by affecting macrophages’
phenotype and invasion processes. Thus, this project preview dissertation will
describe the known mechanisms of invasion and metastasis before discussing why
it cannot yet be prevented due to the not fully elucidated involvement of the
tumour microenvironment. Roles of macrophages in cancer invasion will then be
emphasised and the implication of the extracellular matrix outlined. Finally,
the importance of this project and areas requiring further research will be
discussed.

I)                 
Metastasis:
The Challenge of Breast Cancer

While metastasis is thought to be the cause of 90% of
cancer-related deaths, its mechanisms in cancer pathogenesis remain unclear (Lambert, Pattabiraman and Weinberg,2017). It therefore
represents a crucial target in the fight against cancer.

A)   The
Invasion-Metastasis Cascade

In order for malignant cells to spread from the
primary tumour to the lymphatic or blood vasculature and then to distant
organs, they must acquire migratory and invasive properties (Figure 1)(Chaffer and Weinberg,2011). This complex
multistage process, the so-called invasion-metastasis cascade, relies on a
myriad 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-mesenchymal
transition (EMT), giving them an invasive phenotype (Kitamura and Pollard,2015).
Consequently, the inhibition of TGF-? receptor prevents EMT and invasion in
mammary carcinomas models in vivo, highlighting its key role (Oft, Heider and Beug,1998). Thus, EMT is
characterised 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 caused
by detachment from the ECM (Lamouille, Xu and
Derynck,2014). Finally, this phenotypic shift allows cells to degrade
the ECM of surrounding tissue by secreting matrix metalloproteinases (MMP) and
to move towards lymphatic and blood vessels, where they intravasate after
degrading their basement membrane (Lamouille, Xu
and Derynck,2014). This initial migration towards blood vessels is
therefore crucial for a ductal carcinoma in situ (DCIS) to degenerate into an
invasive ductal carcinoma (IDC) and its prevention could limit the mortality
associated with BC. Thus, findings that macrophages and specific ECM proteins
are overrepresented in tumour stroma will underlie my upcoming investigations
on their hypothesised implication in BC invasion (Acerbi et al.,2015).