Page 24 - Read Online
P. 24
POTENTIAL THERAPEUTIC EFFECT the migration of glioma cells. Additionally, GAS1 has a RGD
OF GAS1 FOR THE TREATMENT OF domain which is essential for the binding and blockade of
GLIOMAS some integrins that promote the migration and invasiveness
of gliomas. [49,135] It has been found that RGD-integrin
Several studies suggest that GAS1 is a tumor suppressor antagonists can inhibit cell adhesion and angiogenesis. [135]
and that its downregulation facilitates the uncontrolled On the other hand, it has been reported that integrin α5β1
growth of several types of cancer cells. [107,108,115-118,124,125] It is (in the absence of attachment to fibronectin) decreased the
worth noting that the downregulation of GAS1 is associated proliferation of HT29 colon carcinoma cells by inducing
with the progression of thyroid and prostate cancer and with the transcription of GAS1. [136] Until now, however, there is
a poor prognosis of survival. [126,127] Additionally the loss no evidence of a relationship between the RGD domain of
of GAS1 increases the metastasis of breast, prostate and GAS1 and cell migration [Figure 2].
gastric cancers. [124,128] On the other hand, GAS1 has been
proposed as a molecular marker for prostate cancer. [129] The recurrence of gliomas that occurs after surgical
The mechanisms that regulate the expression of GAS1 in resection, is attributed to the presence of GIC´s.
gliomas have not been identified yet; however these tumors Alternatively the activation of ERK is involved with the
express several transcription factors that negatively regulate maintenance of the expression of MGMT and resistance
[32]
GAS1 such as c-Myc and v-Src. [56,57] to TMZ of GBM-GICs. As previously mentioned GAS1
inhibits the activation of ERK1/2, thus it may promote the
We previously showed that GAS1 induces apoptosis elimination of the GIC´s population [Figure 2]. It is relevant
and inhibits cell growth in glioma cell lines and human that the overexpression of GAS1 in human adenocarcinoma
glioma primary cultures of low and high grade. [87,88,107,116-118] cells (A549) increases their sensibility to cisplatin,
Furthermore, we demonstrated that GAS1 decreased the which inhibits proliferation and induces cell cycle arrest
proliferation and induced apoptosis through the inhibition and apoptosis. [137,138] Also, the downregulation of GAS1
of AKT as well as the induction of apoptosis mediated promotes resistance to epirubicin in human gastric cancer
by caspase 3, independently of the activity of p53 in C6 by regulating drug efflux and apoptosis. [139] On the other
glioma cells and U373 human astrocytoma cells. [87,88,116-118] hand, it was reported that GAS1 could be an important
Interestingly, GAS1 produces death of glioma cells even biomarker for the prognosis of gastric cancer patients, since
in the presence of the molecular machinery of Shh, it was found that reduced or negative GAS1 expression
[92]
suggesting that it acts through the GDNF pathway [Figure 2]. is associated with shorter survival time and worse patient
prognosis. [124] In conclusion, current data suggest that
Gas1 binds to Ret in a manner independent of the presence GAS1 is a potential adjuvant for the treatment of gliomas
of GDNF. On the other hand, the expression and activity and other tumors. The use of GAS1 with current treatments
[82]
of GDNF and its receptor GFRα1 are increased by their may improve their efficacy.
soluble forms in gliomas. [130-133] Based on the above, we
developed a lentiviral vector in which the expression of Financial support and sponsorship
tGAS1 is inducible. [87,88] This soluble form of GAS1 acts This work was partially supported by CONACYT grant #
both in autocrine and paracrine manners in GBM cells and 239516 (JS).
inhibits glioma tumor growth in vivo. Subsequent to this
study, we used neural stem cells as a vehicle to deliver Conflicts of interest
tGAS1 into intracranial gliomas, since they have innate There are no conflicts of interest.
tropism towards tumors. We found that tGAS1 decreased
tumor growth and increased the overall health and survival REFERENCES
of nude mice implanted with GBM. [88]
1. Ostrom QT, de Blank PM, Kruchko C, Petersen CM, Liao P, Finlay
There is evidence indicating that GAS1 is a metastasis JL, Stearns DS, Wolff JE, Wolinsky Y, Letterio JJ, Barnholtz-Sloan
suppressor in mouse 67NR breast cancer cells and B16-F0 JS. Alex’s Lemonade Stand Foundation Infant and Childhood
melanoma cells. [128] Extracranial metastasis is a rare Primary Brain and Central Nervous System Tumors Diagnosed in the
United States in 2007-2011. Neuro Oncol 2015;16 Suppl 10:x1-36.
manifestation of GBM, this is probably due to the shortened 2. Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky
survival of patients, that will not allow glioblastoma Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical
cells generate metastasis. [134] On the other hand, gliomas report: Primary brain and central nervous system tumors diagnosed in
overexpress ERK1/2 and GDNF, molecules that promote the United States in 2006-2010. Neuro Oncol 2013;15 Suppl 2:ii1-56.
migration and invasiveness of gliomas into the brain 3. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky
parenchyma. [104] There is evidence that GAS1 inhibits the Y, Kruchko C, Barnholtz-Sloan J. CBTRUS statistical report: primary
migration of breast cancer cells by blocking ERK in a brain and central nervous system tumors diagnosed in the United States in
2007-2011. Neuro Oncol 2014;16 Suppl 4:iv1-63.
RET-independent manner. [120] Moreover, GAS1 decreased 4. Larjavaara S, Mantyla R, Salminen T, Haapasalo H, Raitanen
tumor vascularization in a breast cancer model. [120] All these J, Jaaskelainen J, Auvinen A. Incidence of gliomas by anatomic
suggest that GAS1 can be an important molecule to counter location. Neuro Oncol 2007;9:319-25.
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 107