Chemoattraction of Neoplastic Glial Cells with CXCL10, CCL2 and CCL11 as a Paradigm for a Promising Therapeutic Approach for Primary Brain Tumors

Abstract

Chemoattraction is a normal and essential process, but it can also be involved in tumorigenesis. This phenomenon plays a key role in glioblastoma (GBM). The GBM tumor cells are extremely difficult to eradicate, due to their strong capacity to migrate into the brain parenchyma. Consequently, a complete resection of the tumor is rarely a possibility, and recurrence is inevitable. To overcome this problem, we proposed to exploit this behavior by using three chemoattractants: CXCL10, CCL2 and CCL11, released by a biodegradable hydrogel (GlioGel) to produce a migration of tumor cells toward a therapeutic trap. To investigate this hypothesis, the agarose drop assay was used to test the chemoattraction capacity of these three chemokines on murine F98 and human U87MG cell lines. We then studied the potency of this approach in vivo in the well-established syngeneic F98-Fischer glioma-bearing rat model using GlioGel containing different mixtures of the chemoattractants. In vitro assays resulted in an invasive cell rate 2-fold higher when chemokines were present in the environment. In vivo experiments demonstrated the capacity of these specific chemoattractants to strongly attract neoplastic glioblastoma cells. The use of this strong locomotion ability to our end is a promising avenue in the establishment of a new therapeutic approach in the treatment of primary brain tumors.

Drug Delivery Systems in the Development of Novel Strategies for Glioblastoma Treatment

“…Three days after the implantation of the F98 tumor cells, the GlioGels containing the chemoattractant were inoculated. Many peritumoral clusters were observed when CXCL10, CCL2, and CCL11 were implanted in the controlateral hemisphere compared to those implanted in ipsilateral hemisphere [295]. These results support the hypothesis that the use of the GlioGel with chemokines can modify the migration behavior of the GBM cells.…”

“…In 2007, the first clinical trial (NCT00479765) using OncoGel™ for recurrent glioma in order to evaluate the safety and tolerability of the system in the patients started, but could not be ended for sponsor businesses [290]. Déry et al used a biodegradable hydrogel (GlioGel) loaded with three chemoattractants (CXCL10, CCL2, and CCL11) to attract murine F98 and U87 GBM cells toward a therapeutic trap using an agarose drop assay [295]. The zones with high concentrations of CXCL10 display the highest number of the cells attracted compared to the control due to the chemoattractant gradient.…”

“…The zones with high concentrations of CXCL10 display the highest number of the cells attracted compared to the control due to the chemoattractant gradient. CCL2 showed a very similar response to CXCL10 for the F98 cells, but the U87MG cells were less responsive, and both cells did not show any significant effect on chemotaxis to CCL11 [295]. The team performed in vivo assays using an orthotopic syngeneic F98-Fischer rat model.…”

Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma

“…FGF‐1 secretion modulation by graphene could explain the anti‐invasive effect. [ 57 ] Similarly, some of the major pro‐tumoral and pro‐invasive cytokines were also downregulated by rGO‐PEI UT , such as CXCL10, [ 58 ] ang2, [ 59,60 ] thromboplastin, and mmp2 (Figure 7C,D). CXCL10 has been reported to be involved in tumor chemotaxis, mmp2 is related to migration or invasion, then is ang2 and thrombaplastin which related to angiogenesis, comforting thrombosis, and hypoxia are major triggers for invasion.…”

Recent Emerging Immunological Treatments for Primary Brain Tumors: Focus on Chemokine-Targeting Immunotherapies

“…In vitro, CCLs such as CCL2 and CCL5 exhibited a meaningful effect on the attraction and migration of glial tumor cells [ 154 , 155 ]. In glioma U251 cells transfected with CCL2 siRNA, there was decreased cell proliferation, cell cycle arrest, and a significant increase in apoptosis-associated proteins such as Caspase-3 and Caspase-7 [ 156 ].…”