The inverse paradigm and the ancestral cell of IDH-wildtype glioblastoma.

Rethinking IDH-wildtype glioblastoma through its unique features can help researchers find innovative and effective treatments. It is currently emerging that, after decades of therapeutic impasse, some traditional concepts regarding IDH-wildtype glioblastoma need to be supplemented and updated to overcome therapeutic resistance. Indeed, multiple clinical aspects and recent indirect and direct experimental data are providing evidence that the supratentorial brain parenchyma becomes entirely and quiescently micro-infiltrated long before primary tumor bulk growth. Furthermore, they are indicating that the known micro-infiltration that occurs during the IDH-wildtype glioblastoma growth and evolution is not at the origin of distant relapses. It follows that the ubiquitous supratentorial brain parenchyma micro-infiltration as a source for the development of widespread distant recurrences is actually due to the silent stage that precedes tumor growth rather than to the latter. All this implies that, in addition to the heterogeneity of the primary bulk, there is a second crucial cause of therapeutic resistance that has never hitherto been identified and challenged. In this regard, the ancestral founder cancer stem cell (CSC) appears as the key cell that can link the two causes of resistance.

Glioblastoma Unique Features Drive the Ways for Innovative Therapies in the Trunk-branch Era.

Glioblastoma multiforme is a solid tumor with particular aspects due to its organ of origin and its development modalities. The brain is very sensitive to oxygen and glucose deprivation and it is the only organ that cannot be either transplanted or entirely removed. Furthermore, many clues and recent indirect experimental evidence indicate that the micro-infiltration of the whole brain parenchyma occurs in very early stages of tumor bulk growth or likely even before. As a consequence, the primary glioblastoma (IDH-wildtype, WHO 2016) is the only tumor where the malignant (i.e. distantly infiltrating the organ of origin) and deadly (i.e. leading cause to patient's death) phases coincide and overlap in one single phase of its natural history. To date, the prognosis of optimally treated glioblastoma patients remains dismal despite recent fundamental progress in neurosurgical techniques which are enabling better maximal safe resection and survival outcome. Intratumor variegated heterogeneity of glioblastoma bulk due to trunk-branch evolution and very early micro-infiltration and settlement of neoplastic cells in the entire brain parenchyma are the reasons for resistance to current therapeutic treatments. With the aim of future innovative and effective therapies, this paper deals with the unique glioblastoma features, the appropriate research methods as well as the strategies to follow to overcome current causes of resistance.

"The development tumor model" to study and monitor the entire progression of both primary and metastatic tumors.

Glioblastoma multiforme and other malignant cancers resulting in solid tumors continue to be devastating diseases. In order to find more effective treatments, it is necessary to cultivate a better understanding of the dynamics of tumor development in relation to both primary and secondary tumors. Although hand-held or digital caliper methods can measure tumor growth in subcutaneous xenograft models, to date, the only way to follow and monitor the progression of growing tumors in orthotopic animal models is imaging. This is not enough. To improve our knowledge of the biological characteristics that take place during tumor progression at both primary and metastatic sites, it is indispensable to develop an in vivo model which enables us to reproduce, from the beginning to the end of the cancer's natural history, what really happens in a patient affected by a solid tumor. The ideal tumor model must allow us to monitor all the stages of the tumor's development, both in the primary bulk and in secondary locations, by obtaining cells, biopsies as well as performing stainings on sections. In this paper, "the development tumor model", already proposed by the author to monitor the whole progression of the glioblastoma, is also applied to the study of all solid malignancies. It is a xenogeneic orthotopic transplantation model using human tumor-derived cells from the pre-hypoxic phase as transplanted material, which will be cultured in a neurobasal serum-free medium. By transplanting the same material at the same time (time zero) into a number of immunodeficient and genetically identical mice or rats, the model can be used to create a pool of twin animal transplant candidates under the same testing conditions. By sacrificing one animal a week (or choosing other intervals as needed) and performing multiple biopsies and stainings on sections, we can monitor the entire development of both the primary and secondary tumors. This may shed light on which specific cells and particular markers need to be focused on in order to develop innovative, valid therapeutic strategies.

A theory and a model to understand glioblastoma development both in the bulk and in the microinfiltrated brain parenchyma.

The prognosis of patients affected by glioblastoma remains dismal despite many efforts have been devoted worldwide in research and therapeutic strategies. Reasons of our failure include the fact that the patient harboring a glioblastoma always has two problems inside the brain, the bulk tumor and the parenchyma microinfiltrated; the other reason is that the tumor is able to grow dynamically adapting to the mutated conditions of its growth microenvironment. This paper tries to give an interpretation to the dynamic process of the tumor growth, from the beginning to the end of its natural history, dividing it in three phases, one pre-hypoxia and two post-hypoxia, and these are then correlated with the types of cancer stem cells (CSCs) involved. Furthermore, the paper proposes an original animal model to follow glioblastoma development in only one generation of mice, both in the bulk and in the brain parenchyma.