Scientists have identified key molecules that mediate radioresistance in glioblastoma multiforme; these molecules are a potential target for the treatment of this brain cancer.
Glioblastoma multiforme (GBM), is the most aggressive type of brain cancer.
It is treated by radiation therapy combined with chemotherapy. However, even with treatment, the five-year survival rate for GBM is less than 7%.
One of the major causes for this is that GBM rapidly develops radioresistance (resistance to radiotherapy) by unknown mechanisms.
A team of scientists from Hokkaido University and Stanford University have revealed a mechanism by which GBM develops radioresistance.
Their research, published in the journal Neuro-Oncology Advances, explains how two key molecules, Rab27b and epiregulin, interact to contribute to radioresistance in GBM.
The primary function of Rab27b is to regulate protein trafficking and secretion of molecules. Rab27b is also known to promote tumor progression and metastasis in several types of cancer.
For these reasons, the scientists decided to investigate if Rab27b had any role to play in GBM.
Upon performing tests on human glioblastoma cell lines, the scientists showed that Rab27b expression was increased for at least seven days after exposure to radiation. Knockdown of Rab27b increased the sensitivity of glioblastoma cells to irradiation.
These tests were replicated in an animal model: the glioblastoma cells were injected into mice, which were then subjected to radiation therapy. Rab27b knockdown combined with radiation therapy delayed tumor growth and prolonged mouse survival time.
As Rab27b is a regulator of protein trafficking, the scientists continued their work, looking for other molecules that contribute to radioresistance.
They discovered that changes in the expression of Rab27b led to corresponding changes in the expression of epiregulin, a growth factor whose expression is known to increase in cancer cells; knocking down the expression of epiregulin increased the sensitivity to irradiation, as seen in the cells with Rab27b knockdown.
Further, the scientists showed that increased expression of Rab27b and epiregulin in glioblastoma induced the proliferation of surrounding cancer cells, which could contribute to acquiring radioresistance.
Finally, they analyzed gene expression data of GBM patients and found that upregulation of Rab27b and epiregulin correlated with poor prognosis of the patients.
By identifying the roles that Rab27b and epiregulin play in the development of radioresistance in GBM, the scientists have brought to light a novel target for drug development, and one that could significantly increase the survival rate for GBM.
Dr. Jin-Min Nam and Dr. Yasuhito Onodera are part of the Radiation Biology group at the Global Center for Biomedical Science and Engineering (GCB), a collaboration between Hokkaido University, Japan, and Stanford University, USA. The group specializes in molecular and cellular oncology, and radiation biology.
FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2
Glioblastoma (GBM) is the most common and lethal primary brain tumor. Currently, the standard-of-care treatment for GBM patients consists of surgical resection followed by radiation and chemotherapy. Despite these maximal therapies, the median survival of GBM patients is still only 14.6 months.
Therapeutic benefit of irradiation and TMZ treatments is only transient, due in most part to the resistance mechanisms elicited by GBM. Novel therapeutic approaches that can target core oncogenic pathways and/or pathways that confer treatment resistance to tumor cells are urgently needed.
As GBM’s former full name “Glioblastoma Multiforme” refers to, GBM tumor cells reveal highly heterogeneous morphologies and biological properties. A series of recent reports showed that multiple clones with distinct genomic alterations co-exist within a GBM, suggesting clonal diversity is an important factor for intratumoral heterogeneity. [2–6]
On the other hand, glioblastoma stem/or initiating cell (GSC) model postulates cellular hierarchy with GSCs at the apex. These two models are non-mutually exclusive and can bring more comprehensive perspective to our understanding of GBM biology and therapeutics.
Although there are ongoing debates regarding GSC-defining surface marker, frequency, and reversibility of the cellular state, recent studies have suggested that GSCs are critical for GBM propagation and treatment resistance.[7–10] For instance, CD133-enriched GSCs contribute to radioresistance through the enhanced capacity of DNA damage repair.[11, 12]
In addition, GSCs harbor high activation levels of the stem cell regulators and developmental pathways. These pathways include Sox2, WNT, Notch, and hedgehog signaling.
Sox2 is a master regulator of stem cell maintenance in embryonic stem cells, tissue specific stem cells, and cancer stem-like cells. The WNT pathway is critical for self-renewal, proliferation, and differentiation of neural stem/progenitor cells and their progenies in the brain.
We and others have shown the deregulation of WNT pathways in malignant brain tumor [13, 14] and that inhibition of the WNT signaling impedes tumor growth. Indeed, dozens of small molecule inhibitors that can inhibit WNT signaling have been developed for anti-cancer agents.
The forkhead box M1 (FoxM1) transcription factor plays critical roles in developmental processes and cancer by regulating the expression of cell cycle related genes, apoptosis, and DNA damage repair.[15–17] FoxM1 is a key mediator of aberrant WNT signaling in GBM via facilitating nuclear transport of β-catenin.
It also contributes to chemo-resistance by upregulation of the DNA damage repair signaling or MELK-mediated oncogenic signaling.
The role of FoxM1 in chemo-resistance of cancer has been further confirmed in multiple cancer types such as breast [20, 21], lung [22, 23], and colorectal cancer. In contrast, much less is known for the role of FoxM1 in GBM radioresistance.
Several recent reports have suggested that FoxM1 might be more specifically associated with stem cell state in GBM.[13, 19] As GSC targeting is considered as a highly promising approach to treat GBM, FoxM1 inhibition can be an effective mean to target GSC-like cells.
However, molecular links between FoxM1 and core stem cell regulator pathways remain incompletely understood. Based on this background, we investigated functional roles of FoxM1 in the core stem cell pathways and radioresistance.
Utilizing primary patient-derived GBM cells and patient specimens, we showed that FoxM1 activates the stem cell pathways via transcriptional upregulation of Sox2, and this FoxM1-Sox2 signaling axis regulates radioresistance of GBM cells.
reference link :https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137703