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7.5Progression of Cancer, and Metastasis

7.5.1

Progression of Cancer

It is common knowledge that the treatment of cancer becomes difficult if it is left untreated for long. This is not simply because that the size of the tumor grows bigger, but rather because the cancer changes into a more malignant type while it proliferates in its host. Although the expression "more malignant" is not exactly scientific, it signifies properties such as increased metastasis and recurrence, increased chance of functional disorder in the organs with cancer lesions, high rates of cell proliferation combined with resistance to treatment, and immunosuppressive effect on the immune system. This can be interpreted as a result of cancer cells changing in the direction of less differentiation*13.
Apart from changes in both the genomes of cancer cells themselves and their gene expression, changes in the response of the host individual are also related to the progression of cancer. A well-known example of a relationship between the progression of cancer and genes is a phenomenon referred to as acute blastic crisis observed in chronic lymphatic leukemia, a type of blood cancer. Chromosomal abnormalities added to cancer cells augment cell proliferation signals to accelerate the proliferation of cells, eventually replacing normal cells.

*13 As differentiation progresses, cells start exerting their inherent functions and stop moving and proliferating. Meanwhile, undifferentiated cells, in the course of development and differentiation, keep moving toward their destination organs and tissues and proliferate vigorously in order to congregate into a sufficient size. As much as such ability of movement and proliferation is requisite for less differentiated normal cells, this is an onerous property for cancer cells.

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Predisposition Cancer and Family Lineage

Is cancer hereditary? Ordinary cancer is not a hereditary disorder. As has been explained in the main text, genetic abnormalities causing canceration are newly acquired by individuals instead of being inherited from their parents. On the other hand, it is epidemiologically accepted that some families are more "prone to cancer" than others as evidenced by the expressions such as cancer predisposition and cancer family. Although the true nature of such predisposition has not been sufficiently identified, one of the examples currently being postulated is the inheritance of the properties of enzymes engaged in metabolism. Many carcinogens display their carcinogenicity only when they are metabolized after being absorbed into the body. The activity of enzymes responsible for metabolizing these carcinogens is inherited by progeny. Consequently, the same amount of carcinogens may result in a higher chance of causing cancer in some people and a lower chance in others.
In exceptional cases, some cancer is known to be inherited. The presence of abnormalities in the gene of Rb protein described in the main text facilitates the development of cancer called retinoblastoma. The Rb gene of patients with hereditary retinoblastoma is devoid of the function of either a paternal or maternal allele from birth. As a result, adding abnormalities to the other normal allele of the Rb gene is thought to be sufficient in causing cancer. Abnormalities in p53, one of tumor suppressor genes, are also known as a cause of hereditary cancer (Li-Fraumeni syndrome). This disease induces a variety of cancers including leukemia, colorectal cancer, and osteosarcoma, and also stems from abnormalities in either a paternal or maternal allele as in retinoblastoma.

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7.5.2

Cancer Metastasis

One of the prominent phenomena occurring as a result of the progression of cancer is "metastasis," in which cancer cells proliferate to form tumors in organs other than their origin. The majority of cases of the disorder commonly referred to as cancer give rise to epithelium-derived solid tumors. In most cases, excising lesions in a surgical operation is the most effective treatment method available today. It is therefore true that "the prevention of metastasis is tantamount to curing cancer." More importantly, organs in which metastasis frequently occur are usually ones essential for human subsistence such as the lung, liver, brain, and bone. In other words, the majority of deaths from cancer result not from primary foci*14, but from the functional disorder of these organs indispensable for survival because of metastasis.
Cancer metastasis occurs through multiple processes: the movement of cancer cells within tissues, infiltration into the blood vessels such as arteries and veins as well as the vascular channels such as lymph channels, movement within the vascular channels, implantation in different organs, and proliferation and formation of tumor tissue (Fig. 7-5). Important cellular behaviors in these processes include the following characteristics: reduced adhesion between the same type of cells while adhering to other specific cells is generated, heightened mobility, and expression of enzymes on the cellular surface to destroy the structure for maintaining the integrity of tissues such as the basal lamina. Such behavioral characteristics normally belong to immune cells such as leucocytes migrating around the body and embryo-forming cells in the middle of development and differentiation; therefore, they do not intrinsically belong to epithelial cells, which are the origin of solid cancer.

Fig. 7-5. Metastatic Model of Cancer

The state in which cancer cells that have reached the destination organs of metastasis (a small number of cancerous tumors possibly containing platelets and leukocytes) remain at the sites without initiating proliferation is defined as microscopic metastasis or a latent state. The clinical detection of this state is difficult. Although it is not clear how long this state can last, some have reported that it can sometimes continue for 10 years in the case of breast cancer. It has not been clarified perfectly what kind of changes supervenes to cancer cells and host tissues until microscopic metastasis becomes detectable and starts influencing organ functions to the extent that it poses a clinical problem. Through interaction among cancer cells, connective-tissue-forming cells, and inflammatory cells, as well as through the interaction between lymphangiogenesis and immune cells, the occurrences of inflammation, tissue restoration, immune response, and immunosuppression intertwine. Even if cancer is detected and the primary focus is removed surgically, it is mostly the case that microscopic metastases have already been disseminated and hidden covertly. It is therefore expected that an improved method to control these metastases from posing clinical problems after growing into metastatic foci would drastically help advance the results of cancer treatment.

*14 It is the term opposite of metastatic foci of cancer, signifying the sites from which cancer has originated.

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Difference between Cancer Written in Kanji (癌), Hiragana (がん), and Katakana (ガン)

Obviously, these 3 writing styles are used differently in Japan. 癌, which is written in Kanji, or Chinese character, indicates a tumor, especially malignant one, and implies that it is a mass of tissue containing cells with abnormal proliferative ability. The character is said to have originated from breast cancer, a boil developed in normally soft mammary glands. がんwritten in Hiraganam, phonetic characters created at the beginning of the Heisei period, often indicates the disease, that is to say, the state of having developed "cancer or its equivalent." It also includes diseases induced by abnormal proliferative cells which do not form tumors, e.g. leukemia. ガン in Katakana, characters adapted from Kanji used mainly for foreign words, is often used with the overtones or prejudice of abominable incurable disease. Katakana should normally be reserved for scientific terms, yet, in this case, this term has come to insinuate such meaning. Against this background lays the fact that research to understand cancer as a disease has long been lagging behind, and the correct knowledge of the disease has not spread sufficiently. To put simply, "if you eliminate cancer in kanji (癌) completely, you can cure cancer in hiragana (がん) and overcome cancer in katakana (ガン)."

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