Page 4 Complete Your CE Test Online - Click Here be driving them, not just by where they develop in the body or how the cancer cells look under the microscope. As cancer treatments have evolved, genetic testing of cancer tissue can identify specific types of mutations, suggesting potential effective cancer treatments. 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 overexpression of HER2 that can be found by testing biopsy tissue, and those may be treated with these HER2-targeting drugs. 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. 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. As the cancer cells continue to divide and grow, 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. 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 one reason that cancers can be so difficult to 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. 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 earlier. 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) to acquire these nutrients. Genetic mutations, in addition to helping start a cancer, can 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, including 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 downregulated 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 required for rapidly dividing cells and fast-growing tumors. Tumor progression and tumor microenvironments are areas of active research. Although 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. 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. In some cases, treating metastatic cancer may help prolong life although each patient must weigh the pros and cons of such treatment, especially if she will have to deal with the side effects of aggressive treatments near the end of life. Nearly all cancers can form metastatic tumors. Although it is rare, even blood and lymphatic system cancers – such as leukemia, multiple myeloma, and lymphoma – can form metastatic tumors and spread to the lung, heart, central nervous system, and other tissues. Each type of cancer tends to metastasize to common sites. The most common sites of cancer metastasis are the bone, liver, and lung. Although most cancers have the ability to spread to many different parts of the body, each type of cancer typically spreads to a few sites much more often than others. Table 2 shows the most common sites of metastasis, excluding lymph nodes, for some of the more prevalent types of cancer. Table 2. Common cancers and sites of metastasis Cancer types Main sites of metastases* Bladder Bone, liver, lung. Breast Bone, brain, liver, lung. Colorectal Liver, lung, peritoneum. Kidney Adrenal gland, bone, brain, liver, lung. Lung Adrenal gland, bone, brain, liver, other lung. Melanoma Bone, brain, liver, lung, skin/muscle. Ovary Liver, lung, peritoneum. Pancreas Liver, lung, peritoneum. Prostate Adrenal gland, bone, liver, lung. Stomach Liver, lung, peritoneum. Thyroid Bone, liver, lung. Uterus Bone, liver, lung, peritoneum, vagina. *These are listed in alphabetical order both down and across. Brain includes the parenchyma (the neural tissue of the brain) and the leptomeninges (the two innermost membranes that cover the brain and spinal cord, the arachnoid mater, and pia mater; the space between these layers contains the cerebrospinal fluid). Lung includes the parenchyma (the main part of the lung) as well as the pleura, which covers the lungs and lines the chest cavity. Adapted from National Cancer Institute (2013) How cancer spreads A cell’s ability to metastasize is acquired and requires a series of specific changes. Chemokines and their receptors play a role as well: changes in signaling allow some cells to develop a greater capacity for migration and invasion. Cancer cell metastasis usually involves the following steps: 1. Local invasion: Cancer cells invade nearby normal tissue. 2. Intravasation: Cancer cells invade and move through the walls of nearby lymph vessels or blood vessels. 3. Circulation: Cancer cells move through the lymphatic system and the bloodstream to other parts of the body. 4. Arrest and extravasation: Cancer cells arrest, or stop moving, in capillaries at distant locations. They then invade the walls of the capillaries and migrate into the surrounding tissue (extravasation). 5. Proliferation: Cancer cells multiply at the distant location to form small tumors known as micrometastases.