Cancer cells represent the manifestation of a breakdown in any number of normal cell states involving a wide range of cellular processes and cell types, thus the complexity of this disease cannot be understated. Mutations or changes anywhere from somatic DNA, through to active stem cells, as well as epigenetic changes and environmental factors can all contribute to the resulting disease and cancer research areas are just as diverse as these contributing factors. The range of reagents, kits and assays from Meridian support all aspects of cancer research, including oncogenes and genetic markers, epigenetic changes, as well as biomarkers and personalized medicine approaches.
Cancer - a mixed bag of disease states
Our bodies are composed of a broad range of cell types that grow, divide and function in a controlled manner - interacting with other cells to form organized matrices, differentiating into specific types of cells where required and breaking down when damaged or no longer needed.
The processes that control normal cell activity are complex and multi-level and mutations in any number of them can lead to cancer – the continual, unregulated proliferation of cells that grow, reproduce and eventually migrate throughout the body.
There are over 200 different types of known cancers, classified based on the type of cell from which they arise, falling into three main groups:
- Carcinomas – malignancies of epithelial cells, representing over 90% of known cancers and manifesting as abnormal growth of tissue (tumors).
- Leukemias/Lymphomas – produced from blood-forming cells and cells of the immune system, accounting for roughly 8% of human malignancies, suppressing normal blood cell production and immune system function.
- Sarcomas – solid tumors of connective tissues such as muscle or bone, these cancers are relatively rare in humans.
Further classification is based on the type of cell involved and the tissue of origin – for example erythroid leukemias are precursors of erythrocytes. The four most common cancers are breast, prostate, lung and colon, accounting for more than 50% of all cancer cases.
Cancer – mutations within basic cellular processes
The genes within a genome hold the blueprint for creation of the protein molecules that perform many of the important functions of a healthy cell. Mutations within this blueprint have the potential to affect protein production and resulting cellular function.
Meridian offers an excellent range of end-point and real-time PCR reagents and kits to support research into the genomics of cancer and cancer-related mutations. Usually a number of mutations are required before a cell exhibits cancerous properties, typically involving abnormalities in the mechanisms that control cell proliferation, differentiation and survival.
A primary hallmark of cancerous cells is their ability to sustain chronic cell proliferation – growing to high cell densities and larger cell sizes, with limited spatial regulation. Normal cells exhibit density-dependent growth and proliferation, controlled by complex pathways of growth-promotion and inhibitory signalling.
There are a number of ways through which cancer cells can bypass normal proliferative mechanisms including producing their own growth-factor ligands, stimulating neighbor cells to produce various growth factors, or by altering cell surfaces to become hyper-responsive to growth factors. Research in this area looks at a number of different aspects of cell-growth mechanisms, such as mutations that lead to disruptions in the negative feedback mechanisms that reduce proliferative signalling, or those that aid in the evasion of growth suppressors, as well as somatic mutations that activate downstream pathways involved in cell proliferation.
All normal cells are subject to a process called apoptosis, the programmed cell death process that occurs in response to the absence of growth factors or other environmental stimulations, or as a result of DNA damage.
The ability to evade apoptotic processes is another hallmark of cancerous cells, increasing their lifespans and significantly contributing to tumor growth. Upstream regulators and downstream effector components contribute to the apoptotic machinery of the cell environment and consist of both extra- and intra-cellular signalling pathways. There are a number of ways through which tumor cells circumvent or limit apoptosis, such as increasing expression of anti-apoptotic regulators, downregulating proapoptotic factors, or through the total loss of tumor suppressor genes.
Tissue Invasion and Metastasis
Cell-cell interactions and the phenomenon of contact inhibition control the orderly way in which normal cells grow, migrate and adhere to each other to form a healthy cell matrix. In contrast, cancerous cells continue migration regardless of cell contact, growing in multi-layered and disorderly patterns.
In addition, many malignant cells secrete proteases to digest the components of the extracellular matrix and enable invasion of adjacent tissue. Another hallmark of cancer cells is the ability to promote the formation of new blood vessels – angiogenesis – required to supply much needed oxygen and nutrients to the proliferating tumor. The activation of this “angiogenic switch” can be related to factors that either induce or oppose angiogenesis and most likely a number of countervailing factors. The ability to metastasize, that is to migrate or spread to another part of the body not directly connected with the original tumor, involves a complex invasion-metastasis cascade that is still being understood and includes mechanisms that both allow for physical dissemination from the primary tumor, as well as adaptation to the foreign tissue environment at the secondary destination.
Cancer research – genetic predisposition through to personalized medicine
Meridian offers reagents that support all areas of cancer research, from individual reagents and kits for PCR and real-time PCR, through to fully optimized custom designed assays.
Real-Time PCR Assay panels of a full range of miRNA targets associated with cancer-related processes are also available to assist researchers in identifying appropriate targets for further study and ISO 13485 manufactured reagents provide the required quality for developing assays for personalised medicine approaches.
Oncogene/tumor suppressor research
Oncogenes can be defined as any gene or gene cluster, typically involved in an important cellular function such as differentiation, proliferation or apoptosis, which can turn a normal cell cancerous under specific circumstances.
Since the completion of the Human Genome Project and the continued progression of deep sequencing approaches for a range of tumors and cancer types, there has been much hope that identification of key oncogenes would become evident and once identified, ways in which to counter their activation could be devised. What has instead come to light is an unpredicted level of diversity both within and between cancers that have been sequenced thus far. Mutations in several hundred different genes have been identified as drivers of cancer and while data is still being gathered, no clear candidates for subsequent treatment development have emerged thus far, so research efforts continue.
Epigenetic cancer research
The presence of a gene, or indeed a gene mutation, does not necessarily result in subsequent translation of an affected protein.
Physiological or phenotypic variations can be observed in genetically identical cells that contain, for example, differences in DNA methylation or histone modifications, properties that alter the transcriptional potential of a cell. Epigenetic changes can occur as a result of environmental influences, they are heritable as well as reversible and epigenetic changes contribute to carcinogenesis, thus studies in cancer epigenetics are thriving and this area holds promise for the development of cancer treatment options.
Tumor microenvironment research
The tumor, or cancer microenvironment is the cellular environment within which a tumor exists, comprised of immune cells, fibroblasts, blood vessel cells, as well as the proteins produced by these non-cancerous cells that support the growth of cancer cells.
It is difficult to dissociate the microenvironment from traditionally defined cancer cells, however data suggests that dysfunction within the microenvironment is linked to carcinogenesis, thus understanding the pathophysiology of the microenvironment is a path towards development of chemopreventive agents. Research in this area attempts to understand the dynamic and reciprocal interactions between tumor cells and the cells that orchestrate their growth, metastatic properties or drug resistance progression.
Cancer biomarkers and personalized medicine
Biomarkers are biological molecules, such as proteins or nucleic acids, which are found in body fluids or tissues and can be used to assess the state of a biological process, or differentiate normal from disease state.
A wide range of biomarkers for cancer have been identified across the full spectrum of cellular processes involved in the disease and these biomarkers can be used to estimate risk towards developing disease, screen for active disease, determine disease prognoses, and both predict response to therapy and monitor therapeutic responses. There are many researchers committed to unravelling the immense complexity of biological and cellular information that has been collected thus far across the 200-odd diseases that are collectively known as cancer. Insights into this diversity and individual correlations within disease state form the foundation of biomarker development and subsequent personalized medicine. Today almost half of the cancer medicines and treatments in development are linked to small-molecules or novel biologic agents that have been identified as biomarkers for disease and this figure is only likely to increase as research continues in this area.