Can you hear them now? Tumor microtubes form cellular communication networks that protect gliomas from surgical lesions and chemotherapy treatments

See the article by Weil et al. on pages 1316–1326.

Can you imagine how a world of 7 billion people would function if not for the power of communication? From face-to-face verbal interactions, expression via the written word, and more recent advances in electronic media, effective communication is fundamental and vital to growth and success of the human race as a functioning society.

In this issue of Neuro-Oncology, Weil et al¹ provide further strong scientific evidence that malignant brain tumors are no different in their efforts to construct and maintain vast communication networks between cancer cells, allowing them to function as a unified but complex matrix rather than as independent entities (Figure 1). Formation of this extensive cellular network in tumors endows a capacity to effectively resist chemotherapeutic and other treatments that to date have failed to cure high-grade gliomas in the clinic. This publication builds nicely upon the previous report from this group that tumor microtubes (TMs)—long and relatively thin cellular extensions protruding from malignant glioma cells—facilitate cellular invasion, development of radiation resistance, and furthermore may correlate with prognosis based on association with known molecular markers, specifically presence or absence of chromosomes 1p and 19q.² Both studies address head-on the extremely relevant problems of tumor recurrence and chemoresistance of invasive gliomas from a cell biology point of view and open the door to questioning our approaches to both strategies and tactics in treating this patient population.

Fig. 1.

Tumor microtubes contribute to resistance against standard therapies in glioblastoma. Top panel: In treatment-naive gliomas, TMs play multiple roles for tumor invasion, proliferation, and interconnection to one functional tumor cell network. After surgical lesions are induced, gliomas apparently sense the trauma and/or loss of network members, and TMs extend to the lesion area, with nuclei being translocated to that area via the TMs. During chemo- or radiotherapy, TM-connected glioma cells are well protected within the network and survive, while unconnected tumor cells die. Bottom panel: TMs are used to repair surgical lesions. Representative in vivo multiphoton laser scanning microscopy images of mice implanted with T269 human derived glioblastoma stemlike cells (red, cytoplasm; green, nuclei) over a time course of 3 hours, 7 days after induction of a surgical lesion. Note how the tumor cells extend TMs (indicated by arrowheads) toward the lesion area (arrow), which is associated with tumor cell migration in this direction (arrow) and disposition of new tumor cell nuclei (asterisks) which repopulate the lesioned area. Z-stacks of 54 µm. Figure provided courtesy of Dr Frank Winkler.

TMs (a wider and thicker variant of “tunneling nanotubes,” or TNTs, seen in other forms of invasive cancers³) provide a plausible missing link that explains why malignant cells nearly inevitably reorganize into detectable tumors, mostly around the surgical cavity, and why these tumors prove to nearly always be refractory to current standards of care comprising concurrent chemoradiation and adjuvant therapy with temozolomide (TMZ).

In this era of molecular oncology, the field of neuro-oncology can lay claim to O⁶-DNA methylguanine-methyltransferase promoter methylation, presence or absence of isocitrate dehydrogenase mutation, and deletion of 1p and/or 19q as examples of clinically available molecular biomarkers.⁴ Weil et al provide further insight into how these biomarkers affect gliomas at the cellular level, and how cell-to-cell communication induced by microtubes is essentially an aggressive form of stress response to treatment. The researchers made a very important observation regarding disparities in TM formation between TM-rich and TM-poor cells. Two cell lines were both methylated, yet there were differing abilities to form the TM protrusions. To date the field of neuro-oncology in general has not done a detailed exploration of differences in biology or of outcomes within the promoter methylated subset, so it is especially noticeable that there is a difference between cells that theoretically should be susceptible to TMZ. These findings have strong implication for deciphering cell-to-cell communication occurring in high-grade gliomas. For example, gliomas harbor a high degree of heterogeneous subclones distributed spatially throughout tumors⁵; it is conceivable that intercellular communication via TMs induces this intratumoral heterogeneity through shuttling of aberrant signaling proteins. This transport would increase the overall invasive and chemoresistant capacity of these tumors.⁵ Furthermore, TMs may also prove to be potential cellular biomarkers of high-risk low-grade gliomas (LGGs), a category of brain tumors for which optimal treatment approaches remain ill-defined despite recent studies that support adding chemotherapy to radiation for treatment of these patients.⁶ The definition of high-risk LGG remains defined by demographic and radiologic criteria (age >40, contrast uptake on MRI, tumor size >6 cm and/or crossing the midline, etc)⁷—can the presence of TMs be the next defining factor?

For perspective, this is a new and burgeoning field of cancer biology, still in its early stages but ripe with possibilities. It is important to understand that TMs form in the context of a complex, dynamic, and ever-changing heterogeneous tumor microenvironment. To enter clinical relevance to the human patient, it will be critical for researchers to eventually identify the key mechanisms of TM formation, maintenance, and dismantling. The level of potential heterogeneity will be high; the exact underlying key molecular mechanisms will likely differ between cell types and may also even differ between gliomas and other forms of cancers. Studies in the field of TNT biology thus far have tended to focus on specific model systems, so caution must be taken to not automatically assume that a finding in one cell type is automatically applicable to all cell types.

Is there any possibility to take advantage of TMs and TNTs by utilizing them as conduits for drug delivery? Some studies suggest yes. Nanoparticle-bound chemotherapeutic drugs are capable of traveling from cell to cell via TNTs⁸; so are oncolytic viruses. Therapeutic oncolytic viruses have been studied more intensively for treatment of malignant gliomas than arguably any other cancer. The recent discovery that oncolytic viruses can harness TNTs to spread from cell to cell and induce a bystander effect further implies that better understanding the routes and patterns of these “intercellular highways” will permit more efficacious delivery of oncolytic viruses.⁹ In this context, identification of patients whose tumors have more prolific TMs/TNTs may facilitate more selective identification of patients who will best benefit from this and other therapeutic modalities.

This important work by Weil et al provides opportunity to reassess therapeutic strategies and to determine how we can use better understanding of cell biology of gliomas to offer more effective and rationally designed clinical trials to this patient population. In this era of molecular oncology, understanding of cellular biomarkers and their role in causing the challenges we see in the clinical setting is increasing. Altogether, these findings have opened new possibilities into targeting TMs, TNTs, and other similar cellular conduits by using a novel therapeutic strategy: disruption of horizontal cell-to-cell transfer of cellular cargoes that stimulate increased cellular invasive capabilities and chemoresistance. Next steps that would move this field forward include further investigation to determine how this work translates to human gliomas, correlation to known molecular biomarkers, and reassessment of how future trials will take this knowledge into consideration in order to target and disrupt glioma’s communication networks.