7.4Cancer Diagnosis and Pathology
Diagnostic Criteria of Cancer Cells
As has been discussed thus far, the cause of cancer is damage to genes, yet not all cells with damage to their genes are necessarily cancerous. How then is "cancer diagnosis" being conducted in clinical settings to discern the presence of cancer cells? Suppose that there is a tumor in a certain organ, the tumor is excised surgically, and is subjected to pathological examination to determine whether the tumor is malignant or benign, or any part of the tissue shows inflammatory changes. Regular diagnosis depends mainly on histomorphological observation using microscopes. The diagnostic criteria differ depending on the organ. The basic grounds for diagnosing cancer cells are cellular shape, nuclear shape along with the results of dying by various stains, mitotic figures of the cells, relationships with adjacent tissues, etc.
Genetic Diagnosis of Cancer
BRCA1 and BRCA2 are genes deemed to be involved in the incidence of breast and ovarian cancer. According to data reported in the West, 5–10% of breast cancer patients and 2–10% of the whole ovarian cancer patients had abnormalities in these genes. Conversely, it has been conceived that 60–85% of those who had abnormalities in these genes are bound to contract breast cancer, and 25–54% to contract ovarian cancer in their lifetime*11.
In the United States, the genetic testing of BRCA1 and BRCA2 has already been put into practical use with each test costing around 350 thousand yen. Some of the medical institutions in Japan are also performing testing on disease-related genes. Would you like to undergo such a test, or would you hesitate? We would like you to prepare for the foreseeable future in Japan by referring to the actual conditions in the United States described below.
Factually, each gene test ends with single blood sampling. Although many health insurance packages cover the testing costs, a part of the costs will only be reimbursed when the necessity of the testing is acknowledged to be exceptionally high*12. Even in cases where one's family member is a breast or ovarian cancer patient, or cases where one contracts these types of cancer at a young age, the probability of genetic abnormalities actually being detected is not necessarily high. As long as the testing confirms the absence of genetic abnormalities, it will be safe for an examinee to consider that the risks of contracting these cancers are no different from other people; thus that person can be certain for the rest of his/her life—or so it may seem. It should be noted, however, that the testing may produce false-positive or false-negative results, albeit with little possibility. Therefore, just because no abnormality was detected in a test once does not automatically mean that there will be no need for further testing. To begin with, the absence of genetic abnormalities does not necessarily guarantee protection against cancer as the probability entails racial variations as well. In case genetic abnormalities are detected, the following options can be used: to undergo prophylactic bilateral mastectomy, to undergo prophylactic bilateral oophorectomy, to receive medical examinations at least 4 times annually after turning 25 years old, and to receive prophylaxis incorporating hormonal agents.
Surgical treatment, in particular, entails huge implications both physically and mentally. Meanwhile hormone replacement therapy is known to have side effects, which is also the case for other chemical prophylaxes. Medical examinations are not perfect either. Naturally, breast cancer patients who have undergone prophylactic mastectomy face less risk (approximately 1/10) than those who have not. A decrease in the risk can also be recognized in the ovary. Incidentally, it is recommended to receive counseling before undergoing genetic testing.
*11 According to other data reported in the West, 12% of all women who live until 90 years of age developed breast cancer without considering genetic abnormalities.
*12 In the United States, discriminating against insurance applicants on the basis of genetic information is prohibited.
Cancer does not consist strictly of cancer cells alone; as in the case of normal tissues, it comprises connective tissue, blood vessels, lymphatic vessels, and immunological cells. Tissues in the proximity of proliferating cancer cells keep on restoring themselves by means of the same mechanism as repairing of wounds. Consequently, cancer is sometimes referred to as a never-healing wound. In order for it to proliferate, cancer needs to be supplied with nutrition, thus necessitating blood supply from the blood vessels. Many cancer cells release proteins to facilitate vascular growth in a starvation state, thereby prompting neoangiogenesis.
Heterogeneity of Cancer Cells
In spite of the fact that all cancer cells constituting a cancer proliferate from a single cell, they tend to exhibit heterogeneous properties and forms. Even though they originated in the same organ, the manner in which their genes are damaged differs hugely. Similarly, properties of cancer cells and the range of their heterogeneity vary greatly from one cancer to another. Such "individuality of cancer" sometimes serves as a factor to determine how the cancer is going to attack its hosts. A well-known example is scirrhous-type stomach cancer, which is considered dangerous owing to its rapid progression. The nature of this cancer is presumed to derive partly from genetic abnormalities generated in genes that are a part of a series of proteins named cadherin, which is engaged in cell adhesion.
At the same time, it is also true that more often than not a cancer's individuality depends on the nature of the original cells from which the cancer cells originated.
Molecular Target Drugs
Column Fig. 7-3. Action of a Molecular Target Drug Gefitinib
For EGFR to transmit signals for cell proliferation, it needs to be phosphorylated by receiving a phosphate from ATP. When bound to gefitinib, however, EGFR cannot receive a phosphate from ATP, and is thus prevented from sending signals to the cell.
The advancement of molecular biology is starting to bring benefit to cancer treatment as well, namely molecular target drugs. These drugs have been developed in accordance with a treatment strategy based on the understanding of the mechanism of cancer proliferation.
In certain types of cancer such as some lung cancer, activation of the EGF-EGFR pathway plays critical roles in cellular canceration and cancer proliferation. For EGFR to be activated, a reaction called phosphorylation is required. A drug (called gefitinib) that induces cell death by binding to the phosphorylation site of EGFR causing phosphorylation inhibition has already been put to practical use as a cancer treatment drug. Although the efficacy of gefitinib has been substantiated at the cellular level, opinions are divided with regard to its efficacy on actual cancer patients when administered in view of a wide range of perspectives such as cytoreductive effect, life-extension effect, and other side effects.
Chronic myelogenous leukemia, a type of blood cancer, was once feared to be a disease leading to death within a few years of diagnosis. However, the advent of molecular target drugs has made it possible to rescue at least 80% of patients with the disease, thus showing remarkable progress in the field. Since research on numerous drugs is currently still underway, this field has a promising future.