Cancer Essentials is a bi-monthly collection that provides current content on timely topics at the forefront of cancer research and oncology. It’s curated by the editors of Trends in Cancer (Cell Press Reviews) and Elsevier's oncology journals and reference books on cancer.
Cancer is the second killer globally and causes an estimated 9.6 million deaths in 2018, according to the World Health Organization (WHO). Which aspects of these diverse diseases remain challenging to treat?
Cancer stem cells (CSCs), also referred to as tumor initiating cells or tumor propagating cells, are certainly a barrier to progress. CSCs are cancer cells enriched with stem cell features; their functional properties include self-renewal, proliferation and, most importantly, the ability to initiate and regenerate tumors locally and distantly. Accumulating evidence has demonstrated that CSCs are the root of cancer, the seeds of metastases, a source of therapy resistance, and culprits of immune evasion (1, 2).
The challenge: how do we target CSCs for an achievable cure?
Over the last two decades, the understanding of CSCs (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 13), from both patient and mouse tumors and from leukemia to solid tumors, has been greatly facilitated by cutting-edge technologies, including fluorescence-activated live cell sorting, serial transplantation, lineage tracing, high resolution imaging, induced pluripotency reprograming, and single cell genomics and transcriptome analyses. At least three regulatory mechanisms, including genetic, epigenetic and niche alterations, integrate to enable CSC properties and evasive interactions with the immune microenvironment.
Preleukemic or precancerous mutations and genetic aberrations in stem cells selectively pass advantageous properties to progenitors, which may receive the final perturbations for CSC conversion (14, 15, 16). Most cancers, if not all, carry recurrent genetic alterations to drive tumor development. One of the most notable features enabled by genetic changes such as deficiencies of tumor suppressors RB and P53 is tumor plasticity with a conversion from one lineage to another, which can overcome conventional and targeted therapies (17, 18). As a more acceptable and popular term, tumor plasticity is indeed rooted in CSCs: for example, LGR5+ cells of basal cell carcinoma after therapy (19, 20).
Epigenetic and niche regulations have been two prototypical mechanisms to highlight stem cells and CSCs. Some low mutation burden tumors lack recurrent genetic changes (21), thus emphasizing the importance of epigenetic reprogramming in cancer phenotypic development. Best known stemness signaling pathways include Wnt, Hedgehog, Notch, Nanog, Hippo/YAP and or STAT3 (22, 23, 24). The epigenetic landscape for cellular reprograming not only derives from alterations in chromatin and DNA methylation (24) but also interactions with themselves (25) and the microenvironment (24). Moreover, CSCs and many stemness promoting factors evade immune recognition and suppress immune attacks (1, 26, 27, 28, 29). Both genetic and non-genetic changes, epigenetically and post-transcriptionally, intrinsically and extrinsically, drive CSC dynamic and plastic phenotypes to adapt for advantageous fitness, escape from immune attacks, metastasize for distant colonization, and resist various therapies.
Due to their heterogeneity and plasticity, targeting of CSCs has been challenging and yet to be widely and clinically achieved. Nevertheless, successful examples include Hedgehog inhibitor vismodegib, which has been FDA-approved for basal cell carcinoma treatment. Many new CSC-targeting drugs are still under pipeline production and in clinical trials.
In the battle against cancer, our appreciation of cancer mechanisms and targeting approaches for CSCs have deeply and comprehensively evolved since 1990s. This evolution is also shared by CSCs that continue to respond to new therapies developed to neutralize self-renewal. Next-generation therapeutics that do not kill CSCs seem to make them stronger and fitter.
How can we win the race? We hope this series of papers inspires generations of scientists and advocates to join us and address the question.
Cancer Essentials – stem cells
Cancer stem cells - an overview
- Overview: Cancer Stem Cell Self-Renewal, Maider Zabala, Neethan A. Lobo, Dalong Qian, Linda J. Van Weele, Diane Heiser, Michael F. Clarke, Cancer Stem Cells (First Edition)
- New Opportunities and Challenges to Defeat Cancer Stem Cells, Erika K. Ramos, Andrew D. Hoffmann, Stanton L. Gerson, Huiping Liu, Trends in Cancer
- Epigenetics and Cancer Stem Cells: Unleashing, Hijacking, and Restricting Cellular Plasticity, Elanor N. Wainwright, Paola Scaffidi, Trends in Cancer
- Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis, Srikanth Barkeer, Seema Chugh, Surinder K Batra, Moorthy P. Ponnusamy, Neoplasia
- Developing Cures: Targeting Ontogenesis in Cancer, Victor T.G. Lin, Hawley C. Pruitt, Rajeev S. Samant, Lalita A. Shevde, Trends in Cancer
Hematopoietic stem cells and blood cancers
- Modeling Normal and Disordered Human Hematopoiesis, Philip A. Beer, Connie J. Eaves, Trends in Cancer
- Age-associated changes in human hematopoietic stem cells, Pang, W.W., Schrier, S.L., Weissman, I.L., Seminars in Hematology
- Critical Updates to the Leukemia Stem Cell Model, Yogen Saunthararajah, Cancer Stem Cells (First Edition)
- Exploring Stem Cell Heterogeneity in Chronic Myeloid Leukemia, Chinmay Munje, Mhairi Copland, Trends in Cancer
Stem cells in solid tumors
- Cancer Stem Cells as New Therapeutic Targets for Ovarian Cancer, Yinu Wang, Fang Fang, Salvatore Condello, Daniela Matei, Kenneth P. Nephew, Cancer Stem Cells (First Edition)
- Lung cancer stem cells: The root of resistance, Lauren MacDonagh, Steven G.Gray, Eamon Breen, Sinead Cuff, Stephen P. Finn, Kennet J. O'Byrne, Martin P. Barr, Cancer Letters
- Stem Cells, Cancer, and MUSASHI in Blood and Guts, Michael G. Kharas, Christopher J. Lengner, Trends in Cancer
- Differentiation and Inflammation: ‘Best Enemies’ in Gastrointestinal Carcinogenesis, Nathan M. Krah, L. Charles Murtaugh, Trends in Cancer
- Developmental Insights into Breast Cancer Intratumoral Heterogeneity, Mei Zhang, Jeffrey M. Rosen, Trends in Cancer
- Breast Cancer: Multiple Subtypes within a Tumor? Syn Kok Yeo, Jun-Lin Guan, Trends in Cancer
- Cancer stem cell in breast cancer therapeutic resistance, Xupeng Bai, Jie Ni, Julia Beretov, Peter Graham, Yong Li, Cancer Treatment Reviews
- Multifaceted Roles of Interleukin-6 in Adipocyte–Breast Cancer Cell Interaction, Jones Gyamfi, Minseob Eom, Ja-Seung Koo, Junjeong Choi, Translational Oncology
- Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets, Guang-Ning, Yan Yang-Fan Lv, Qiao-Nan Guo, Cancer Letters
- Molecular Events in the Natural History of Pancreatic Cancer, Leslie E. Oldfield, Ashton A. Connor, Steven Gallinger, Trends in Cancer
Stem cells: metastasis and therapy resistance
- Metastasis and Metastatic Cells: A Historical Perspective and Current Analysis, Kiera Rycaj, Dean Tang, Cancer Stem Cells (First Edition)
- Cancer Stem Cells: Metastasis and Evasion From the Host Immune Responses, Avijeet S. Chopra, Xia Liu, Huiping P. Liu, Cancer Stem Cells (First Edition)
- Surviving at a Distance: Organ-Specific Metastasis, Anna C. Obenauf, Joan Massagué, Trends in Cancer
- The Mechanisms of Therapy Resistance in Cancer Stem Cells, Chihsuan Chang, Jeffrey M. Rosen, Cancer Stem Cells (First Edition)
- Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement, Rashmi Bharti, Goutam Dey, Mahitosh Mandal, Cancer Letters
- Adaptive Stress Responses During Tumor Metastasis and Dormancy, Daniela Senft, Ze'ev A. Ronai, Trends in Cancer
Modeling and tools to study cancer stem cells
- Modeling Cancer with Pluripotent Stem Cells, Julian Gingold, Ruoji Zhou, Ihor R. Lemischka, Dung-Fang Lee, Trends in Cancer
- Circulating Tumor Cells, Cancer Stem Cells, and Emerging Microfluidic Detection Technologies With Clinical Applications, Molly Kozminsky, Sunitha Nagrath, Cancer Stem Cells (First Edition)
- Targeting Biophysical Cues: a Niche Approach to Study, Diagnose, and Treat Cancer, Shirley X. Zhang, Linan Liu, Weian Zhao, Trends in Cancer
Our guest contributors
Huiping Liu, MD, PhD
Dr. Liu received a medical degree (MD) and MS in Biochemistry & Molecular Biology from China. She obtained a PhD in Biomedical Sciences (cancer biology) at the University of Chicago in 2006 with Dr. Kay Macleod as her thesis Advisor. Following a passion for cancer stem cells (CSCs) and microRNAs, Dr. Liu completed her postdoctoral training with Dr. Michael Clarke at Stanford University and Dr. Geoffrey Greene at the University of Chicago. Her work demonstrated that breast CSCs play an important role in cancer metastasis and identified microRNA suppressors of breast CSC-mediated chemo-resistance and metastasis. From 2013 to 2016, Dr. Liu established her independent research program at Case Western Reserve University, focusing on understanding breast CSCs and exosomes in metastasis, developing exosome-based diagnostic biomarkers and nano-therapeutics.
Since January 2017, Dr. Liu has joined Northwestern University Feinberg School of Medicine. Dr. Liu has a primary appointment in Department of Pharmacology and a secondary appointment in Department of Medicine, Hematology/Oncology as a member of the Lurie Comprehensive Cancer Center. The Liu laboratory continues their basic and translational research programs on CSCs and exosomes: (1) to understand CSCs in metastasis using cutting-edge single cell sequencing and gene editing technologies; (2) to investigate CSC social behavior (cluster formation) and their interactions with immune cells during metastasis using bioluminescence and intravital imaging; (3) to elucidate exosome functions in cancer stemness and immune regulation; (4) to develop stemness-indicating circulating biomarkers (circulating tumor cells and exosomes) and CSC-targeted therapeutics.
Justin Durla Lathia, PhD
Dr. Justin Lathia leads a translational cancer stem cell research laboratory and is an Associate Professor in the Department of Cellular and Molecular Medicine at the Lerner Research Institute, part of the Cleveland Clinic. Dr. Lathia is a native of central Pennsylvania and received a B.S. and M.S. from Drexel University in Philadelphia, PA in 2003. While at Drexel, he developed targeted ultrasound contrast agents which preferentially bound to newly formed vessel in breast cancer models. After graduation from Drexel, Dr. Lathia completed his Ph.D. as part of the NIH-Cambridge Graduate Partnership Program. His worked focused on the role of cell adhesion molecules during the development of the nervous system.
After completing his PhD in 2008 he completed post-doctoral fellowships at Duke and the Cleveland Clinic where he focused on the role of cell adhesion in regulating cancer stem cells in brain tumors. In 2012, Dr. Lathia moved to the Department of Cellular and Molecular Medicine as an independent investigator and the work in his lab focuses on how the stem cell state is regulated in advanced cancers. Projects in the Lathia laboratory involve understanding how cancer stem cells interact with their surrounding microenvironment as well as one another with the goal of identifying unique pathways for therapeutic development. Work in the Lathia laboratory has resulted in a Phase 1 clinical trial aimed at targeting myeloid-derived suppressor cells that interact with cancer stem cells to suppress the immune system in glioblastoma.
Dr. Lathia has co-authored over 135 publications and work in his lab is currently supported by multiple National Institutes of Health grants and foundation grants. Dr. Lathia also contributes as a peer reviewer to over 105 journals, serves on the editorial board of Cell Reports and Neuro-Oncology, and has served on multiple grant review panels for the National Institutes of Health and private foundations. He recently served as a co-editor for a cancer stem cell textbook. Dr. Lathia also serves as a co-organizer for the cancer stem cell meeting held in Cleveland in 2014, 2016 and 2018. At each meeting, the-3 day event drew over 300 attendees from over 25 states and 15 countries.
Drs. Liu and Lathia are editors of the textbook Cancer Stem Cells, exploring targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance.