Page 4 Complete Your CE Test Online - Click Here insignificant mutations can produce diseases, for example, an inherited defect in one gene can cause Huntington’s Disease [26, 215]. Often, the initial genetic mutations that lead to cancer arise during a person’s lifetime. These acquired mutations are only present in the abnormal cells, and are called sporadic or somatic mutations. They can result from errors that occur as cells divide, i.e. every time a cell divides there is a chance of this kind of error, or because of damage to DNA caused by certain environmental exposures [26]. Cancer-causing environmental exposures include substances such as the chemicals in tobacco smoke, and radiation, such as X-rays and ultraviolet rays (UV) from the sun [202] (see “Cancer risk factors”). Acquired mutations can accumulate over a lifetime, which is part of the reason why older people have a higher risk of cancer. Even an individual with a germline mutation that predisposes that person to cancer need additional genetic mutations before cancer results. The germline mutation provides the foundation of abnormal genetics for acquired mutations to build on. This can speed up the process of cancer development, and is one of the reasons that inherited cancer syndromes often produce cancer earlier in life [26]. Proto-oncogenes, tumor suppressor genes, and DNA repair Genetic changes that contribute to cancer tend to affect three main types of genes: proto-oncogenes, tumor suppressor genes, and DNA repair genes. These changes are sometimes called “drivers” of cancer [202]. Proto-oncogenes are involved in normal cell growth and division. However, when these genes are mutated in certain ways or become more active than normal, they may “go rogue” and become permanently activated. If that occurs they are considered cancer-causing genes (oncogenes), which allow cells to divide and survive when they should not [202]. Tumor suppressor genes are involved in controlling cell growth and division. When tumor suppressor genes are mutated and if this inactivates them, it can cause cancer or allow a cancer to grow. A prominent example is the TP53 gene, which produces the P53 protein [266]. The P53 protein, among other functions, prevents damaged cells from reproducing. This is an important role, since damaged cells are more likely to contain mutations that lead to cancer. The inactivation of this tumor suppressor gene plays a role in more than half of all cancers [26]. DNA repair genes are involved in fixing damaged DNA. Cells with mutations in the DNA repair genes tend to develop additional mutations in other genes. Together, these mutations may help the cells to become cancerous [202]. As scientists have learned more about the molecular changes that lead to cancer, they have found that certain mutations occur in many types of cancer. For example, in order for a solid tumor to grow more than two millimeters (mm), i.e. about the size of a pinhead, it must develop a blood supply [302]. However, there are multiple pathways to develop a blood supply. Cancers are now sometimes characterized by the types of genetic alterations that are believed to be driving them, not just by where they develop in the body and/or how the cancer cells look under the microscope [202]. As cancer treatments have evolved, genetic testing of cancer tissue can identify specific types of mutation, suggesting potential effective cancer treatments [26]. For example, the HER2 proto-oncogene normally helps cells grow, but when too many copies of the gene occur, HER2 becomes an oncogene (HER2 is an acronym for human epidermal growth factor receptor 2, also known as ERBB2). Women who have breast cancer with this particular oncogene do not respond well to certain types of standard chemotherapy, but there are newer drugs that specifically target HER2. Breast cancer tissue is now tested to determine if the patient will benefit from drugs such as trastuzumab, lapatinib, and pertuzumab. Certain stomach cancers also have an over expression of HER2 that can be found by testing biopsy tissue, and those may also be treated with these HER2-targeting drugs [26]. Genetic changes in cancer initiation and progression Each cancer has a unique combination of genetic changes. Cancer begins with one abnormal cell that survives and begins to divide out of control. In order for this to happen, there must be changes in the signaling around the cell, so that the cell can bypass the usual controls on cell growth [302]. As the cancer cells continue to divide and growth progresses, all of which must be supported by the microenvironment around the cell, additional genetic mutations occur. The newly-mutated cells divide along with the abnormal cells that arose earlier in the process. This means that even within the same tumor, different cells may have different genetic changes so that there are different clones (clone in this sense refers to a group of identical cells that share a common ancestry) of abnormal cells in the cancer [202]. In cancer development, certain mutations may allow some of the cell lines to divide more quickly, to spread more easily, or to evade immune detection more readily. Some mutations even allow for increased resistance to cancer therapy. This is one reason cancer cells respond to different drug treatments in different ways, and also one of the reasons that cancers can be so difficult to completely eradicate. Advanced cancers have even more variety among their cells, increasing the risk that some of the various mutation patterns of the cells may be more resistant to certain treatments [55]. Cancer progression Cancer progression is generally unchecked before effective treatment is started. The malignant cells continue to divide relatively rapidly as the cancer grows, with mutations that confer various advantages to certain cell lines as noted above. These changes mean that the cancer growth may speed up over time, and that certain cell lines may predominate in the cancer. During this time, solid cancers must establish methods for increasing circulation so that nutrients can reach the tumor and nourish its growth. The cancer cells must have what they need to grow, and they exert direct effects on the tumor microenvironment (the area directly around the cancer cells) in order to acquire these nutrients. Genetic mutations, in addition to helping start a cancer, can also increase the production of substances that favor cancer growth or inhibit cellular signaling substances that slow growth. Chemokines are a subset of cytokines which use chemical signals to direct cellular activity. Normally, chemokines are involved in many cellular activities, such as cell migration (e.g. white blood cells trafficking to sites of infection), normal cell growth, and immune responses. Chemokines and their receptors can behave abnormally in cancer, and play important roles in cancer progression and metastases. They can become involved in tumor growth, angiogenesis, evasion of immune detection, and metastasis. For example, chemokines and chemokine receptors that normally induce cell senescence (death of abnormal cells) can be mutated or down regulated in ways that promote tumorigenesis rather than interfere with it. Certain types of cancer cells secrete chemokines that promote growth. Chemokines can support or promote angiogenesis, and forming new blood vessels is a requirement for rapidly-dividing cells and fast-growing tumors [253]. Tumor progression and tumor microenvironments are areas of active research. While it is well known that there are chemokines that normally inhibit tumor cell proliferation, more studies are needed to find out how chemokines and their receptors are co-opted in ways that promote tumor growth and progression. This kind of research might help identify more targets for future treatments. Cancer metastasis Metastasis is a complex process by which certain cancer cells leave their primary site and enter the bloodstream or the lymphatic system to grow elsewhere. Under the microscope, metastatic cancer cells generally look the same as cells of the primary cancer. Moreover, metastatic cancer cells and cells of the original cancer usually have some molecular features in common, such as the expression of certain proteins or the presence of specific genetic mutations [176]. Although a few types of metastatic cancer can be cured with current treatments, it is rare. Treatments are available for patients with metastatic cancer, but the main goal of those treatments is typically to control the growth of the cancer or to palliate symptoms [176]. In some