Dr Nobue Itasaki
Embryos and cancer share similar features such as rapid growth, active cell migration, and changes in the differentiation state. However, embryos’ highly regulated development contrasts with cancer’s aberrant growth and destructive cellular behaviour. How much are they similar and what make them different?
The pathological condition of cancer is modulated by various micro-environmental factors. The major constituent of microenvironment, extracellular matrix (ECM), surrounds tumours directly thus giving strong impact on cell growth, morphology, migration and function. ECM is mainly produced by fibroblasts, which can evolve with adjacent cancer cells to establish microenvironment which supports further cancer growth. Activation of inflammatory pathways also promotes malignant transformation, progression of the disease and metastasis. To the contrary, embryonic microenvironment does not allow grafted cancer cells to grow, despite the genetic lesions imprinted in the cells. We aim to find out the mechanism whereby embryonic microenvironment attenuates cancer-specific cellular behavior.
Project on cancer cells
In order to examine microenvironmental factors, it is essential to have an in vitro system in which cancer cells readily exhibit a malignant morphology and alter their gene expression profile in response to exogenous signals. Recently my group has been successful in in vitro three-dimensional (3D) culture system. This allows us to monitor cancer cells’ morphological changes and interaction with non-cancerous cells by time-laps filming for over 72 hours (Videos 1,2). We are now studying the effect of various candidate factors on the cancer cell behavior.
Breast cancer cells (MDA-MB-231, green) interacting with spheres of non-cancerous epithelial cells (MDCK, red). Movie 1 represents an initial stage of interaction, where cancer cells appear to inspect non-cancerous cells.
Movie 2 represents a late stage of interaction, where cancer cells engulf non-cancerous cells. (F. Owolabi, L. Ivers, N. Itasaki, unpublished. More movies are available on; Ivers et al. Cancer Cell Int. 14, 108, 2014;
Project on embryonic development
Neural crest cells are a group of cells transiently seen during embryogenesis. They arise from dorsal neural tube by epithelial-mesenchymal transition (EMT), acquire motility, migrate and differentiate into peripheral nerves as well as major skeletal components of head and neck structures. EMT is partly analogous to cancer metastasis, sharing the molecular mechanism for cell dissociation. However, it is not clear how EMT in embryos is tightly regulated temporally and spatially, while in cancer it is not. We recently found that hypoxia, which occurs transiently during development prior to vasculogenesis, promotes emigration of neural crest cells. This is reminiscent of the fact that local tissue hypoxia in cancer promotes metastasis. Hypoxic cellular response is exerted by activation of Hypoxia Inducible Factor (HIF)-dependent transcriptional activation, both in adult and embryos. We are currently investigating the role of HIF1 pathway on neural crest cells. This will offer insights into the similarity and difference in regulating cell transformation between embryos and cancer.
Chick embryos grown in ovo (A), ex ovo (B) and ex ovo in the presence of dimethyloxaloylglycine that stabilizes HIF protein thus mimicking the hypoxic cellular response (C). Embryos are stained for Sox10 by RNA in situ hybridisation. The embryo grown ex ovo hence exposed to ambient air shows reduced neural crest cells (B) compared to the in ovo cultured one (A). Note that Sox10 expression in the otic vesicles is not reduced. Dimethyloxaloylglycine restores induction of neural crest cells (C).