Cancer Stem Cells: A New Way To Look at an Old Disease

Jaime Modiano, VMD, PhD; University of Minnesota

 

Cancer and Public Health. Undoubtedly, cancer is among the conditions that will have the most significant impact on the health and well being of people and their pets during the 21 st century. The entity that is cancer has been recognized since the times of the ancient Greeks, but it was only in the latter part of the 20th century that we began to understand why cancer happens. As the art and science of medicine and veterinary medicine reduced morbidity and mortality from other causes and the expected lifespan increased, cancer became more prevalent in the human and canine populations. Today, cancer is the leading cause of death in people under the age of 85, and it is the most common cause of disease-related death in dogs. It is estimated that ~ 30% of people and dogs will get cancer in their lifetime, and in dogs, more than half of those affected will die from their disease.

 

Despite these grim statistics, we cannot ignore advances that we have achieved in diagnosis and treatment of cancer. With proper standard of care, cancer patients can reasonably expect to add at least 10% of a lifetime after their diagnosis and many patients survive cancer and lead normal, productive and healthy lives. Because cures are difficult to define, the treatment goal today is to make cancer a manageable chronic disease. Improved application of existing therapies (surgery, chemotherapy, and radiation), as well as new therapies coming on line can achieve this for a large number of patients. However, sometimes the price is too high - either because the side effects are unacceptable or because the treatment is cost prohibitive. Both of these are greater obstacles in veterinary medicine, where quality of life is paramount and where health care reimbursements from insurance are not the norm. It is this segment of the population, then, that most preoccupies us and fuels our desire to continue probing the inner workings of cancer so that we can realistically design better strategies to prevent, diagnose, and treat this condition.

 

Cancer as a Disease of Stem Cells. With that background, we can appreciate the importance of thinking outside the box. What if we ask questions about why we fail so often, as opposed to trying to incrementally build on small gains? It is this type of thinking that has led to a revised theory about the origins of cancer that may revolutionize how we approach this disease.

 

For >40 years we have known that cancers arise from a single cell (clonal expansion) and that a series of mutations are necessary for the cell of origin to acquire the malignant phenotype. However, the dominant theory assumed that all cells possessed an equal capacity for self-renewal (see below for definition). It also assumed that proliferation was a stochastic ("random") process driven entirely by environmental selection of favorable mutations. However, self-renewal and differentiation potential are the key elements that define what a stem cell is. So a competing theory now exists whose main tenet is that cancer is a consequence of malignant transformation of cells that retain properties of stem cells, but harbor defined mutations that endow them with malignant properties. It is not entirely a different concept, but simply a different way of looking at the same data, and it is intellectually satisfying because it explains much about cancer that was difficult to reconcile with the old models.

 

What is a Cancer Stem Cell? The first and most important thing to note is that normal stem cells, such as those harvested for regenerative therapies are!!!!! the same as cancer stem cells. The American Association for Cancer Research (AACR) convened a Workshop in February, 2006 to achieve a consensus definition of a cancer stem cell. Based on that workshop, the consensus definition was "a cell within a tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor." For this reason, it is important to define cancer stem cells based on their ability to recapitulate a continuously growing tumor. In essence, this means a tumor that can be serially passaged in vivo (in a laboratory mouse) by one (or very few) cell(s), and thus the term in its strictest definition is synonymous with "tumor- initiating cell" or "tumorigenic cell". The term "cancer stem cell" is somewhat unfortunate as it can easily be interpreted mean that such cells derive from stem cells of the corresponding tissue. In fact, cancer stem cells may indeed arise from normal stem cells by mutations that make them cancerous, but this may not be the case in all tumors. That is, it is possible that more differentiated cells can acquire the capacity for self-renewal and become immortalized through multiple mutations, so it is this differentiated cell, and not the tissue stem cell, that eventually evolves to become a full-blown cancer stem cell.

 

It is important to note that proliferation is not the same as self-renewal. A self-renewing cell division results in one or both daughter cells (progeny) that have essentially the same ability to replicate and generate differentiated cell lineages as the progenitor cell. Stem cells can undergo symmetrical self-renewing division, causing identical daughter cells that retain "sternness" or self-renewal capacity, or asymmetrical self-renewing division, resulting in one stem cell and one more differentiated progenitor cell that can continue along a defined lineage or lineages. It also is possible that some stem cells may divide symmetrically to form two progenitor cells, leading to stem cell depletion. Promoting this latter form of division would be a way to deplete the cancer stem cell population by differentiation, and may hence constitute an alternative strategy to inducing cell death to treat cancer.

 

Do Cancer Stem Cells Really Exist? The existence of cancer stem cells is now documented; they are characterized by peculiar phenotypes, by defined sets of genetic mutations, and by their ability to form tumors that can be serially passaged in laboratory animals. In the case of lymphoma or leukemia, <1 in 250,000 tumor cells has the properties that define a cancer stem cell. Similar results have been obtained for a variety of solid ,tumors, although much work remains to be done to define the "cancer stem cell" for many types of cancer.

 

Clinical Implications of Cancer Stem Cells. The cancer stem cell model can explain various paradoxical findings regarding tumors and their natural history. It accounts for the relatively small number of genes that are disproportionately associated with a multitude of cancers, for the ability of multicellular organisms (like people and dogs) to reach reproductive age and attain

long lives without cancer, and perhaps most importantly, for the observed nature of tumor relapse and metastasis. Cancer stem cells divide infrequently and are thus resistant to most of the types of treatments we use for cancer (which rely on killing rapidly dividing cells). Even though they divide rarely, cancer stem cells have the potential to regenerate the full complement of progeny that originally comprised the tumor. Thus, failure to eliminate cancer stem cells with - or after cessation of - chemotherapy sets the stage for tumor re-growth and relapse, which would not occur if the surviving cells lacked the capacity for self-renewal). The acquisition of additional mutations, possibly due to the therapy itself, allows the remaining cancer stem cells to generate new progeny with enhanced survivability in novel environments, favoring aggressive, metastatic phenotypes. This suggests that, in order to achieve sustained remissions, we will need to devise treatment regimens that target the cancer stem cell compartment.

 

Cancer Stem Cells and Canine Tumors. The stem cell theory of cancer has not been conclusively proven in dogs, but we have seen subpopulations of cells in hemangiosarcoma and in lymphoma that have phenotypes consistent with stem cell origin. For hemangiosarcoma, we extended these observations to define a phenotype that firmly established the bone marrow origin of this tumor, and allowed us to distinguish hemangiosarcoma cells from other bone marrow-derived cells and from normal circulating endothelial cells. This led to the development of a useful diagnostic test for hemangiosarcoma. More recently, we have shown that the tumors harbor specific subpopulations that retain the "primitive" (stem cell-like) characteristics and may harbor unique gene expression signatures. In fact, the relative frequency of these cells may explain the observed differences in the clinical behavior of these tumors. Our current work focuses on defining these cancer stem cell populations and their usefulness to predict responses to standard of care, as well as to identify new treatments to effectively target these cells. The premise that appropriate activation of the immune system might be able to eliminate both the cancer stem cells and their progeny is among the concepts that we plan to explore in an ongoing clinical trial for osteosarcoma that is supported jointly by the NCI and the AKC CHF.

 

Biographical Profile

 

Dr. Jaime Modiano hails from Mexico City, where he graduated from the baccalaureate program at Colegio Columbia. He did undergraduate work in Biomedical Sciences at Texas A&M University in College Station, TX for three years before moving on to veterinary school at the University of Pennsylvania. He completed his veterinary training and PhD in Immunology at Penn, followed by a residency in Veterinary Clinical Pathology at Colorado State University, and a post-doctoral fellowship at the National Jewish Center for Immunology and Respiratory Medicine in Denver, CO. He was appointed to the faculty in the Department of Veterinary Pathobiology at Texas A&M University as Assistant Professor between 1995 and 1999. Dr. Modiano returned to Denver from 1999 to 2007; there, he held Scientist and Senior Scientist appointments at the AMC Cancer Research Center and he was Associate Professor of Immunology and Full Member of the Cancer Center at the School of Medicine of the University of Colorado Health Sciences Center. In July of 2007, Dr. Modiano joined the College of Veterinary Medicine, School of Medicine, and Comprehensive Cancer Center at the University of Minnesota, where he continues his research program as Professor of Comparative Oncology holding the Al and June Perlman Endowed Chair.

 

Between 2001 and 2003, Dr. Modiano served as Director of Cancer Immunology and Immunotherapy for the Donald Monk Cancer Research Foundation; he also is a partner at Veterinary Research Associates, LLP, a company focused on development and implementation of diagnostics for veterinary medicine and a founder/scientist at ApopLogic Pharmaceuticals, LLC, a biotechnology company focused on development of cancer therapeutics. His research program has had uninterrupted support from federal and private sources for 13 years, leading to co-authorship of more than 50 peer-reviewed scientific manuscripts, and ~200 abstracts, presentations, and book chapters focused on various aspects of immunology, cancer cell biology, the genetic basis of cancer and applications of gene therapy.

 

Dr. Modiano is married to Dr. Michelle Ritt, a board certified specialist in Veterinary Internal Medicine. They share their home with Logan, a champion agility Gordon setter and Quetzal, a German Shepherd Dog.

 

Dr. Modiano 's research has been supported by the following grants.

 

1626T: Significance of Tumor Suppressor Genes in Canine Cancer

2254A: Heritable and Sporadic Genetic Lesions in Canine Lymphoma and Osteosarcoma 615A-T: Heritable and Sporadic Genetic Lesions in Canine Lymphoma

947B: Heritable and Sporadic Genetic Lesions in Canine Osteosarcoma

 

Cancer Stem Cells – conference notes

 

There is no reason to doubt or fear therapeutic stem cells.  However, cancer stem cells are its evil twin.

 

A comparative approach to Cancer

            Everything we learn from dogs we can use in humans, everything we learn in humans we can use in dogs

 

What is cancer?

            A group of diseases defined by uncontrolled proliferation

                        2^nd cause of death in children and adults under 85 years old

            Originates from a single cell

 

Fundamental problem is that the cell retains or gains the ability to undergo self-renewal and loses the ability to fully differentiate

 

What causes cancer?

            Life – anytime your cells divide, they can cause cancer

 

What are risks of cancer?

            Life!

 

The Breen and Modiano Axiom:

“Cancer may an inevitable consequence of mammalian evolution – nature has only so many tools to work with.  Evolution is a risk of cancer.”

 

Descriptive aspects of cancer in dogs

            Lifetime risk ~1 in 2 or 1 in 3

            About 50% of deaths for dogs over 10 years old

            Most common cause of disease-induced death

            Treatable, most cases probably not preventable with currently available strategies

Cannot prevent cancer with “internet” remedies

But do take healthy steps to avoid cancer “cells” – limit sun exposure, stop smoking (2^nd hand smoke does affect dogs), maintain lean body mass along with a good exercise program

            There are differences amongst breeds.

High risk (lymphoma): boxer, golden retriever, Labrador retriever, Scottish terrier, basset hounds, saint bernards, Doberman pinschers, German sherpard dogs, and some others

                       

Low risk: mutts, Pomeranians, poodles, Chihuahuas (other small breeds), etc.

           

            Frequency of lymphoma diagnosis in relation to age - avg is 9.5 years old +- 3.2 years

                        Goldens on average diagnosed at 8.5 years old +- 2.9 years

                        Rottweilers on average diagnosed at 6.8 years old +- 2.3 years

                        Boxers on average diagnosed at 8 years old +-2.6 years

                        Labradors on average diagnosed at 8.5 years old +- 3 years

                        Cocker spaniels on average diagnosed at 10.2 years old +-3.7 years

            Frequency of osteocarcoma diagnosis in relation to age – avg is 8 years old +- 2.7 years

                        Goldens on average diagnosed at 7 years old +- 3.2 years

                       

There are some gene markers that can now be identified to see who will survive longer with lymphoma.

 

Where does cancer come from?

            Cancer arises when a cell accumulates a series of mutations that:

                        Enable self-sufficiency from growth factors

                        Disengage sensitivity to anti-growth signals

                        Allow cells to evade programmed suicide

            There is no single cause of cancer

            Many or most of the popularity held beliefs about cancer causation are false

            Environmental – caustic compounds and chemicals

                        Smoking, however only about 20% of smokers ever develop cancer

 

Evidence for cancer stem cells:

- Self renewing population maintains tumors like chronic lymphocytic leukemia and multiple myeloma

            - Only the stem cell compartment can replicate the disease

- Stem cell progeny that are unrelated to the tumor carry mutations associated with the tumor

            *if the hypotheses holds that only stem cells carry cancer, then we could be targeting the wrong cells.  Which means we need to be able to manage the stem cells appropriately.