Malignant Transformation of Cells

Treatment of normal cultured cells with chemical carcinogens, irradiation, and certain viruses can alter their morphology and growth properties. In some cases this process, referred to as transformation, makes the cells able to produce tumors when they are injected into animals. Such cells

VISUALIZING CONCEPTS

VISUALIZING CONCEPTS

(a) Initially modified tumor cell

Basal lamina

Blood vessel

(b) Mass of tumor cells (localized benign tumor)

(a) Initially modified tumor cell

Basal lamina

Blood vessel

(b) Mass of tumor cells (localized benign tumor)

Invasive tumor cells

Invasive tumor cells

Tumor cells invade blood vessels, allowing metastasis to occur

Tumor cells invade blood vessels, allowing metastasis to occur

FIGURE 22-1

Tumor growth and metastasis. (a) A single cell develops altered growth properties at a tissue site. (b) The altered cell proliferates, forming a mass of localized tumor cells, or benign tumor. (c) The tumor cells become progressively more invasive, invading the underlying basal lamina. The tumor is now classified as malignant. (d) The malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body. [Adapted from J. Darnell et al, 1990, Molecular Cell Biology, 2d ed, Scientific American Books.]

are said to have undergone malignant transformation, and they often exhibit properties in vitro similar to those of cancer cells. For example, they have decreased requirements for growth factors and serum, are no longer anchorage-dependent, and grow in a density-independent fashion. Moreover, both cancer cells and transformed cells can be subcultured indefinitely; that is, for all practical purposes, they are immortal. Because of the similar properties of cancer and transformed cells, the process of malignant transformation has been studied extensively as a model of cancer induction.

Various chemical agents (e.g., DNA-alkylating reagents) and physical agents (e.g., ultraviolet light and ionizing radiation) that cause mutations have been shown to induce transformation. Induction of malignant transformation with chemical or physical carcinogens appears to involve multiple steps and at least two distinct phases: initiation and promotion. Initiation involves changes in the genome but does not, in itself, lead to malignant transformation. After initiation, promoters stimulate cell division and lead to malignant transformation.

The importance of mutagenesis in the induction of cancer is illustrated by diseases such as xeroderma pigmentosum. This rare disorder is caused by a defect in the gene that encodes a DNA-repair enzyme called UV-specific endonuclease. Individuals with this disease are unable to repair UV-induced mutations and consequently develop skin cancers.

A number of DNA and RNA viruses have been shown to induce malignant transformation. Two of the best-studied are SV40 and polyoma. In both cases the viral genomes, which integrate randomly into the host chromosomal DNA, include several genes that are expressed early in the course of viral replication. SV40 encodes two early proteins called large T and little T, and polyoma encodes three early proteins called large T, middle T, and little T. Each of these proteins plays a role in the malignant transformation of virus-infected cells.

Most RNA viruses replicate in the cytosol and do not induce malignant transformation. The exceptions are retro-viruses, which transcribe their RNA into DNA by means of a reverse-transcriptase enzyme and then integrate the transcript into the host's DNA. This process is similar in the cyto-pathic retroviruses such as HIV-1 and HIV-2 and in the transforming retroviruses, which induce changes in the host cell that lead to malignant transformation. In some cases, retrovirus-induced transformation is related to the presence of oncogenes, or "cancer genes," carried by the retrovirus.

One of the best-studied transforming retroviruses is the Rous sarcoma virus. This virus carries an oncogene called v-src, which encodes a 60-kDa protein kinase (v-Src) that catalyzes the addition of phosphate to tyrosine residues on proteins. The first evidence that oncogenes alone could induce malignant transformation came from studies of the v-src oncogene from Rous sarcoma virus. When this oncogene was cloned and transfected into normal cells in culture, the cells underwent malignant transformation.

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