Abstract:
Metabolic stress at the cellular and organismal level may play a significant role in
oncogenesis. Lipid-dependent metabolic stress in the extracellular matrix (ECM) has
been linked with tumour initiation and metastasis. Previous work has identified the
involvement of certain lipid raft molecules like Caveolin-1 in educating sites for
metastasis. The fat receptor CD36 in lipid rafts similarly interacts with several ECM
molecules, including integrins and is a key upstream regulator in lipid metabolism and
collagen degradation leading to the pathogenesis of CD36-mediated signalling that
disrupts ECM homeostasis. Oral Submucous Fibrosis (OSF) is a debilitating,
potentially malignant condition of the mouth with 7-13% transformation rate, which
is frequently found in South Asia and in the Western-Pacific. It is caused by Arecanut
chewing, which progressively restricts mouth opening that contributes to dietrelated
metabolic stress leading to anaemia and vitamin and protein deficiencies. OSF
is marked by epithelial atrophy and fibrosis with accumulated type I collagen in the
submucosa undergoing inflammation and reactive immune responses but little is
known about the process of malignant transformation. We hypothesized that
dysregulated fat metabolism might be a key denominator in the malignant
transformation of OSF and CD36 as a fat biosensor may play a pivotal role in the
intracellular and extracellular signalling pathways. We analysed patient data with quid
chewing frequency and restricted mouth opening and found that the clinical
presentation of malignant transformation was strongly associated with the number of
betel quids (7-12 or more) used per day. Epithelial thickness increased in 3 folds with
the development of oral cancer compared with OSF and OSF-dysplastic stages
predominantly characterised by atrophy. Immunohistochemistry with CD36 in OSF
showed localization with epithelial cell nuclei adjacent to the basement membrane,
while a remarkable elevation of CD36 was seen across tumour cell cytoplasm in the
invading islands. Taken together, these suggested how a functional shift in CD36 may
result in the malignant transformation of those cells undergoing metabolic stress.
Further studies will validate how CD36-dependent cancer initiation favours tumour
cell survival and metastasis under metabolic stress conditions.
