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J Cancer Metastasis Treat 2016;2 Suppl 1

epithelial/cancer stem cells are identified as CD44+, Tumors are complex tissues and cancer is a disease
CD133+, α2β1 integrinhigh. Integrin α2β1 is a collagen characterized by aberrant differentiation as much
receptor, which proposes that cell-collagen interaction as it is of disturbed proliferation. Tumor cells are
is important for the stem cell biology in prostate. phenotypically plastic, and an unsolved issue in
However the role of specific ECM proteins and cellular cancer biology is to what extent the expansion of
receptors in regulating prostate stem cells remains cancer stem cells representation that accompany
poorly understood. tumor progression is caused by expansion of pre-
existing stem cells or, rather, by a differentiation block
Here, we have used primary cultures of prostate- or even de-differentiation of more differentiated tumor
derived fibroblastic cells, allowed them to generate cells. Indeed, the molecular mechanisms that preserve
ECM, these matrices and specific matrix proteins differentiation or induce cell plasticity in neoplastic or
(collagen I and fibronectin) were used to examine normal tissues, as in the case of acquisition of stem-cell
prostate cancer cell-line DU145 proliferation and drug traits by more mature cells during tissue repair, remain
resistance to widely used anti-mitotic chemotherapy unknown. At this meeting, I will present new evidence
drug docetaxel. Sorting cells to sub-populations based indicating the role of YAP e TAZ, transcriptional effectors
on their expression of α2β1 integrin allowed us to of Hippo- mechano- and Wnt-signaling, in regulating
investigate whether higher expression of α2β1 integrin cell plasticity. It appears that these properties of YAP/
is in consistence with theory that cells with high α2β1 TAZ are independent of acquisition of a mesenchymal
integrin are more resistant to cytotoxic drugs. To study phenotype, require interaction with chromatin and are
thoroughly the role of α2β1 integrin on prostate cancer shared by multiple cell type, including non-epithelial
stem cells, we created α2 integrin knock-out of DU145 ones. Notably, in mouse models, YAP/TAZ are
cell-line by CRISPR/Cas9 system and compared it with essential for normal stem cells of breast, pancreas
wild-type DU145 cells and rescued cells, which were and neural tissues when these are activated by tissue
transfected with plasmid carrying α2 integrin construct. damage in vivo, or for growth as organoids ex vivo. In
these are other tissues, this correlate with the genetic
Our results present that ECM-cancer cell interaction requirement of YAP/TAZ to initiate tumorigenesis. The
reduced proliferation of cancer cells however according modalities of YAP/TAZ regulation by Wnt and other
to EC50 values had no effect on the resistance to upstream cues will be also discussed.
docetaxel. The EC50 values on collagen I were 18.8
± 0.3; on fibronectin: 19.5 ± 0.2; on fibroblast-derived Key words:
ECM: 19.6 ± 0.3. Based on collected data we concluded YAP/TAZ, cancer stem cells, Wnt signalling, cell
that there was no protective feature of fibroblast- plasticity
derived ECM to DU145 cancer cells from docetaxel
induced cell death. Cells that survived docetaxel A22
treatment presented significantly higher expression of Use of 3D spheroid cultures to screen for
α2 integrin and CD44, suggesting enrichment of stem- drugs targeting cancer stem cells
like cell population. Indeed, the sub-population with
high expression of α2β1 integrin had slightly better Juan Gumuzio, Olatz Leis, Angel G. Martin
survival rates. The ongoing study on whole genome
sequencing of CRISPR/Cas9 modified DU145 cells StemTek Therapeutics, Derio, Spain
will reveal the differences in gene expression and may
bring to light some new properties of integrin signaling. The cancer stem cell (CSC) concept has important
implications not only for our understanding of
Key words: carcinogenesis, but also for the development of cancer
Prostate cancer stem cells, α2β1 integrin, drug therapeutics. There is a growing body of preclinical
resistance, CRISPR/Cas9 system, extracellular matrix, evidence showing that cancer stem cells contribute
cancer associated fibroblasts to chemotherapy and radiation resistance in breast
cancer. The use of drugs that interfere with stem cell
A21 self-renewal represents the strategy of choice for
YAP/TAZ, transcription factors at the roots of novel effective anti-cancer treatments, but also a great
cancer challenge because cancer stem cells and their normal
counterparts share many pathways.
Luca Azzolin, Michelangelo Cordenonsi, Stefano Piccolo
The biology of cancer stem cells has proven complex
Department of Molecular Medicine, University of Padova, Padova, Italy and difficult to translate into effective therapeutic
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ November 16, 2016 429