Elsevier

Seminars in Cancer Biology

Volume 82, July 2022, Pages 162-175
Seminars in Cancer Biology

Cancer cell heterogeneity & plasticity in glioblastoma and brain tumors

https://doi.org/10.1016/j.semcancer.2021.02.014Get rights and content

Abstract

Brain tumors remain one of the most difficult tumors to treat and, depending on the diagnosis, have a poor prognosis. Of brain tumors, glioblastoma (GBM) is the most common malignant glioma and has a dismal prognosis, with only about 5% of patients alive five years after diagnosis. While advances in targeted therapies and immunotherapies are rapidly improving outcomes in a variety of other cancers, the standard of care for GBM has largely remained unaltered since 2005. There are many well-studied challenges that are either unique to brain tumors (i.e., blood-brain barrier and immunosuppressive environment) or amplified within GBM (i.e., tumor heterogeneity at the cellular and molecular levels, plasticity, and cancer stem cells) that make this disease particularly difficult to treat. While we touch on all these concepts, the focus of this review is to discuss the immense inter- and intra-tumoral heterogeneity and advances in our understanding of tumor cell plasticity and epigenetics in GBM. With each improvement in technology, our understanding of the complexity of tumoral heterogeneity and plasticity improves and we gain more clarity on the causes underlying previous therapeutic failures. However, these advances are unlocking new therapeutic opportunities that scientists and physicians are currently exploiting and have the potential for new breakthroughs.

Introduction

A study published in 2017 by the National Cancer Institute found across-the-board improvements in 5-year survival for patients with cancer from the 1970s to 2013 (except for cervical and uterine cancer) [1]. However, even with this improvement in survival, patients with brain tumors still have only a 30 % survival at 5 years after diagnosis, and this number is far worse for some tumors types, such as glioblastoma (GBM) in adults and diffuse intrinsic pontine glioma (DIPG) in children.

The brain and spinal cord are the most well-protected organs in the body and are evolutionarily designed to be protected from damage as much as possible throughout one’s lifetime. In addition, each region of the brain has a specific function and can cause serious physical or mental disability when perturbed. These truths lead to various challenges that are not seen in other regions of the body when attempting to treat tumors within the central nervous system (CNS). An obvious example of this is that neurosurgeons must first maneuver through the skull and, when in the parenchyma, must resect the tumor with as narrow margins as possible to limit debilitating comorbidities.

This review will discuss the many ways by which our understanding of brain tumors has evolved and prevented scientists and clinician from developing treatments that improve long-term survival. We will focus on the high levels of heterogeneity and plasticity in GBM and other brain tumors as well as discuss new therapeutic avenues that have been exposed due to the exponential growth in our understanding of these tumors.

Section snippets

Overview of brain tumors

It is estimated that between 10–20 % of patients with cancer will be diagnosed with a brain metastasis, and autopsy studies have reported a true incidence of 30–40 % in all patients with cancer [[2], [3], [4], [5]]. A total of 67–80 % of brain metastases come from either lung, breast, or melanoma primary tumors. In all three of these tumors, the presence of brain metastases portends a poor survival. The median survival of patients with brain metastasis has been observed to be 13 months [6], and

Molecular heterogeneity of glioblastoma

It has long been observed that GBM possesses extensive inter- and intra-tumoral heterogeneity. Early histological studies of GBM focused on the extent of necrosis, nuclear size, astrocytic differentiation, cell size, number of mitotic cells, distribution of cell density and vascularization [26]. Through this approach and the sampling of various locations within the tumor, scientists and pathologists were able to observe significant histological variations even within the same tumor. This

Epigenetic heterogeneity in glioblastoma

While advances in our understanding of the genetics and expression patterns of GBM have enabled vertical advancements in the field, these advances have yet to result in changes in the clinical management of GBM, and the five-year survival remains around 5% [57]. Additionally, the GLASS consortium finding that mutations at recurrence are largely random suggests that mutational evolution is not driving therapeutic resistance and plasticity in GBM. This has led many in the field to investigate

Cancer stem cells

Any discussion of GBM heterogeneity and plasticity is not complete without a discussion of the CSC population. CSCs are a population of tumor cells that are defined by their functional ability to self-renew, initiate tumors, and undergo persistent proliferation [31,67]. There is no single marker of CSCs in GBM, however the glycoprotein CD133 was initially found to mark a CSC population and is widely used for sorting tumor cells today [68,69]. Furthermore, it was discovered that those with a

Glioblastoma interaction with non-tumor cells

One fact that has been understood for many years is that the GBM microenvironment consists of more than merely tumor cells. Numerous other cell populations within the brain and the immune system contribute to the conditions that lead to tumor growth. These populations include endothelial cells, microglia, astrocytes, neurons, and immune cells. The failure of many tumor cell targeting therapies has led scientists and physicians to investigate the potential of targeting other cells within the

Conclusion

Brain tumors are among the most heterogeneous tumors to have been characterized. From early histological studies that documented regions of necrosis to more recent single-cell RNA sequencing and methylation profiling, GBM is a tumor with resounding intra- and inter-tumoral heterogeneity. In addition, heterogeneity at the level of cell type, the sex and age of the patient, and plasticity over time all add to the complexity of the disease. Unfortunately, this lack of homogeneity or single driver

Funding source

Work in the Lathia laboratory is supported by the Cleveland Clinic, Case Comprehensive Cancer Center, the American Brain Tumor Association, National Brain Tumor Society, and NIH R01 NS109742, R01 NS117104, and P01 CA245705. Adam Lauko is supported by the Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship F30 CA250254. Alice is supported by a summer research scholarship provided by CWRU SOURCE with additional funding provided by the Women in Science and Engineering

Declaration of Competing Interest

Manmeet Ahluwalia declares the following: grants/research support-Astrazeneca, Abbvie, BMS, Bayer, Incyte, Pharmacyclics, Novocure, Mimivax, Merck. Receipt of honoraria or consulting fees: Elsevier, Wiley, VBI, Vaccines, Bayer, Tocagen, Novocure. Shareholder: Doctible, Mimivax, Cytodyn.

Acknowledgements

We regret that we were unable to include all work on glioblastoma, cancer stem cells, cellular heterogeneity, and plasticity in this review due to spatial limitations. We would like to thank the members of the Lathia laboratory for insightful discussions. We thank Ms. Amanda Mendelsohn for illustration assistance and Dr. Erin Mulkearns-Hubert for editorial assistance. Work in the Lathia laboratory is supported by the Cleveland Clinic, Case Comprehensive Cancer Center, the American Brain Tumor

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