David J. Argyle, BVMS, PHD, DECVIM-CA (Oncology), MRCVS
Cancer is a disease of all vertebrate species and is well documented throughout history, with fossil records indicating dinosaurs of the Jurassic period suffered from the disease. The Greek physician, Galen is accredited with describing human tumours of having the shape of a crab, with leg like tendrils invading deep into surrounding tissues, hence the term cancer. Today cancer can be defined as any malignant growth or tumour caused by abnormal and uncontrolled cell division, able to invade tissues locally and able to spread to other parts of the body through the lymphatic system or the blood stream. This is obviously a simplistic attempt at describing a complex disease that can utilize a myriad of biological pathways to sustain growth and proliferation. Dissecting these pathways has been the challenge of cancer researchers for decades in the search for new treatment strategies. However, despite the identification of key molecular pathways in cancer, the disease remains one of high mortality and morbidity. Radiation and conventional chemotherapy are still (despite their side-effects) the mainstays of treating advanced local and disseminated disease.
The Basic Biology of Cancer
For many years, cancer researchers have considered a stochastic model of cancer development. In this, cancer formation is the phenotypic end result of a whole series of changes that may have taken a long period of time to develop. Following an initiation step produced by a cancer-forming agent on a cell, there follows a period of tumour promotion. The initiating step is a rapid step and affects the genetic material of the cell. If the cell does not repair this damage, then promoting factors may progress the cell toward a malignant phenotype. In contrast to initiation, progression may be a very slow process, and may not even manifest in the lifetime of the animal. Over the past four decades, cancer research has generated a rich and complex body of information revealing that cancer is a disease involving dynamic changes in the genome. Each stage of multi-step carcinogenesis reflects genetic changes in the cell with a selection advantage that drives the progression towards a highly malignant cell. The age-dependent incidence of cancer suggests a requirement for between four and seven rate limiting, stochastic events to produce the malignant phenotype
The Complexity of Cancer
However, the last two decades of cancer research have demonstrated that, despite the many potential causes of cancer and carcinogenic pathways, transformation of a normal cell into a malignant cell actually requires very few molecular, biochemical and cellular changes. These changes can be considered as the acquired capabilities of a cancer cell that allow it to be regarded as displaying a malignant phenotype. Further, despite the wide diversity of cancer types, these acquired capabilities appear to be common to all types of cancer. An optimistic view of increasing simplicity in cancer biology is further endorsed by the fact that all normal cells, irrespective of origin and phenotype carry similar molecular machineries that regulate cell proliferation, differentiation, ageing and cell death. Consequently, we can consider that the vast array of cancer genotypes is a manifestation of only seven alterations in cellular physiology that collectively dictate malignant growth. These characteristics are acquired during the process of carcinogenesis and can be considered as:
A self sufficiency in growth
An insensitivity to anti-growth signals
An ability to evade programmed cell death (apoptosis)
Limitless replicative potential (mainly through reactivation of telomerase)
An ability to sustain angiogenesis
An ability to invade and metastasize
An ability to evade host immunity
It is important to stress that the pathways for cells becoming malignant are highly variable. Mutations in certain oncogenes can occur early in the progression of some tumours, and late in others. As a consequence, the acquisition of the essential cancer characteristics may appear at different times in the progression of different cancers. Furthermore, in certain tumours, a specific genetic event may, on its own, contribute only partially to the acquisition of a single capability, whilst in others, it may contribute to the simultaneous acquisition of multiple capabilities. Irrespective of the path taken, the hallmark capabilities of cancer will remain common for multiple cancer types and will help clarify mechanisms, prognosis and the development of new treatments.
Identifying Key Targets
With advances in molecular and cell biology techniques, we have identified a number of genes and proteins that are key players in the processes described above. This has been coupled with gene and tissue array technologies, which have enabled a "systems biology" approach to identifying key interacting pathways in malignant development. One area that has received considerable attention is that of the Tyrosine Kinase Pathways.
Receptor Tyrosine Kinase Targets
The growth and differentiation of cells is tightly regulated through the activity of specific signal transduction molecules. The Receptor Tyrosine Kinases (RTK's) are a specific group of protein kinases that are expressed on the cell surface and are activated through the binding of specific growth factors. Normal kinase function is critical to cell growth and differentiation, and has also been implicated in new blood vessel formation in tumours (Angiogenesis) and the process of metastasis. Dysfunction of several RTK's has been characterized in a variety of cancers, and can occur through mutation, overexpression, creation of fusion proteins and the development of autocrine loops. Given the widespread characterization of RTK dysregulation in cancer, and the central role that these molecules play, the RTK family lend themselves as obvious targets for specific cancer therapy. In human medicine, two approaches have been adopted for cancer therapy, and are proving successful in clinical trials (e.g., Herceptin and Gleevec). In veterinary oncology, two RTK inhibitors have now been approved for use in the treatment of mast cell disease in dogs and this is the first targeted therapy available for veterinary species.
Why Are We Failing
Despite the advent of targeted therapies, the success rates of these drugs are, at best, around 30%. This suggests that we have a long way to go before making significant impacts on survival. Major problems exist with regards:
Cancer rapidly evolve to develop resistance to both chemotherapy and targeted drug therapy
Cancer is heterogeneous
We do not fully understand the mechanisms of cancer development and metastasis
Identifying disease at its earliest stage is still a major obstacle to successful therapy
It is likely that multimodality therapy will have the greatest likelihood of success
Questions have recently been raised about whether we are actually targeting the correct population of cells in cancer and have suggested that cancer is a true stem cell disease
Stem Cells and Cancer
For decades, the accepted model of carcinogenesis has been a stochastic model whereby any cell in the body has the potential for malignant transformation. However, this model is sometimes difficult to reconcile with what happens in the animal body. The majority of cells making up the various organ systems have a finite life-span, dictated largely through progressive telomeric attrition at each cell division. The question then comes as to how a cell would live long enough to acquire the number of mutations required to become a cancer cell? A challenge to the stochastic model is the cancer stem cell theory, which suggests that cancer is, in fact, a true stem cell disease. If this is the case, then the implications are immense:
Stem cells demonstrate resistance to many conventional treatments, such as chemotherapy and radiation.
Leukaemic stem cells have demonstrated resistance to drugs such as Gleevec despite having the BCR-ABL translocation.
The suggestion is that these cells may harbor specific molecular targets that need to be overcome before a significant impact is made on cancer mortality rates.
Epithelial to Mesenchymal Transition
In recent years it has emerged that carcinoma cells rely on a mechanism "borrowed" from normal stem cell biology for invasion and metastatic spread. In this, cells at the leading edge of a tumour undergo an epithelial to mesenchymal transition (EMT), which triggers cellular motility and subsequent dissemination of tumours cells. Significantly, induction of EMT in normal or neoplastic epithelial cell populations has been shown to result in the enrichment of cells with stem cell-like properties. Increasing evidence indicates that EMT plays an important role in acquisition of cancer stem cells, metastatic progression, and therapeutic resistance. Therefore, EMT-induced processes offer a clinically important therapeutic target, whereby inhibition of EMT may have a significant effect on disease outcome. Further work is needed to dissect out the signalling networks that regulate the induction and reversibility of EMT.
Cancer drug discovery seems to follow a continuous sine wave that varies between optimism and pessimism. However, our understanding of the complexity of cancer is increasing at an exponential rate. We are now seeing the emergence of the first targeted therapies for cancer in veterinary species. However, it is naïve to think that these therapies will significantly improve mortality rates. It is, however, the first steps at developing a multifaceted approach to targeting cancer at its fundamental core. With an increased understanding of some of the stem cells and EMT pathways in cancer, a more optimistic view is that we will soon see much improved therapies for all species.