How cancer stem cells form – the role of ErbB receptors
By Charlotte Harrison, Science Writer
Cancer stem cells are thought to be key drivers of tumour formation and progression. If we can pinpoint the mechanisms by which cancer stem cells form, this understanding could lead to better cancer treatments. A new paper published in Scientific Reports shows that ErbB2/ErbB3 tyrosine kinase receptors are crucial players in the formation of cancer stem cells.
Modelling cancer stem cell conversion
Revealing the exact mechanisms behind cancer initiation is challenging since it requires us to study events that occur very early during tumorigenesis. The researchers behind the current study used a previously established method that allows them to investigate the development of cancer stem cells. Their method involves converting mouse pluripotent stem cells (miPSCs) into cancer stem cells using cell culture media from cancer-derived cells to mimic the cancer-inducing microenvironment that occurs in the body.
In the current study, the researchers studied the formation of cancer stem cells in a pancreatic cancer microenvironment. First, they used RNA-seq analysis to compare gene expression patterns between miPSCs and pancreatic cancer stem cells. Genes with the highest change in expression were related to the ErbB2/ ErbB3 signalling pathway; namely ErbB2 and ErbB3 receptors, and their ligands Nrg-1 and Nrg-2. ErbB2 and ErbB3 receptors, which function as a heterodimer, are known to be overexpressed in many cancer types and are linked to tumour grade, relapse, and resistance to treatment.
Stopping stemness and tumorgenicity
To assess the role of ErbB2/ErbB3 signalling during the formation of cancer stem cells, the researchers used lapatinib to inhibit ErbB2, a compound called TX1-85-1 to inhibit ErbB3 or receptor-targeted siRNAs. These treatments suppressed the conversion of miPSCs into cancer stem cells. Moreover, blocking ErbB2/ErbB3 signalling greatly reduced the expression of stem cell markers such as Oct3/4 and CD24, and increased MAP kinase; these results showed that ErbB2/ErbB3 signalling has an important role in the development of stemness.
Moreover, lapatinib inhibited tumour angiogenesis, which is an essential hallmark of cancer. In particular, lapatinib blocked the formation of tube-like structures by iPSCs, showing that ErbB2/ErbB3 signalling is involved in tumorigenicity.
Together, these results highlight that activation of ErbB2/ErbB3 signalling is a key point in the conversion of normal stem cells into cancer stem cells in conditions that mimic the pancreatic cancer microenvironment. This new insight might one day be used to predict or treat pancreatic cancer.
Image Credit: Canva
