This excerpt from the book Invasion and Metastasis (from "The Molecular Basis of Cancer") highlights why the spread of cancer is the most life-threatening attribute of the disease. While tumors confined to their original tissue have near 100% cure rates, spreading or metastasis often renders the cancer incurable.
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Swarnali Acharyya, Lynn Matrisian, Danny R. Welch, and Joan Massagué
Invasion and Metastasis
In the written history of medicine, neoplasnis have been diagnosed for nearly 4000 years. Almost from the begin-ning, medical practitioners recognized that the most life-threatening attribute of neoplastic cells is the ability to disseminate and colonize distant tissues. When tumors are diagnosed and have not spread beyond the tissue of origin. cure rates for most cancers approach 100%. However, when tumor cells have established colonies elsewhere, cancer is often incurable.
The process of converting a normal cell into a life-threatening metastatic cancer cell is referred to as tumor progression (Figure 18-1). As discussed in previ-ous chapters, medicine has evolved toward a recognition that neoplasia is a cellular disease, and further advanced to understand the molecular underpinnings of the early stages of progression resulting in cancer development. It is now recognized that metastases represent a subset of cells that have left the primary tumor, which are behavior-ally distinct from the cells remaining at the site of tumor origin, and the molecular mechanisms underlying the phe notypic differences that characterize a metastatic cell are being elucidated.
Generation of a Metastatic Cell
Metastasis is defined as the dissemination of neoplas-tic cells to discontiguous nearby or distant secondary sites where they proliferate to form a mass. But how did tumor cells acquire the ability to metastasize? The answer to this question requires examination of the mechanisms underly-ing how tumors arose and progressed toward increasingly aggressive behavior.
By the time a neoplasm is diagnosed, it comprises ar least 10 cells. Yet, even cursory examination of a tumor his-tologically reveals that the cells are pleiomorphic. Further more, if one isolates single cell clones from a tumor, they vary dramatically in terms of biological behavior.
Tumor heterogeneity exists for virtually every phe-notype measured. There are three types of heterogeneity within a tumor: positional, temporal, and genetic. Positional heterogeneity is determined by the accessibility of a cell to external stimuli (e.g., oxygen [O2] levels). For example, radiation sensitivity is proportional to oxygenation; there-fore, two identical cells would exhibit differences in radio-response depending on distance from a capillary. Temporal heterogeneity is relevant with regard to changes in cells due to cyclical signals. Cells in the Go/G₁ phase of the cell cycle would be less sensitive than cells in the S phase to drugs tar-geting DNA replication. Genetic heterogeneity is the result of inherent properties of tumor cells themselves. Isolation of single-cell clones confirms that there are inherent differ-ences between subpopulations comprising a single tumor mass.
The heterogeneity of tumors raises an important ques-tion regarding tumor origin: Are tumors of unicellular or multicellular origin? Tumors express maternal or paternal isoenzymes, but rarely both, strongly suggesting that they arose from a single cell. Analysis of karyotypes reveals that virtually ali cells within a tumor share a common abnormal chromosomal change (e.g., all CML, cells have t(9:22]). Additional karyotypic abnormalities may be superimposed on the shared ones. If tumors are monocional, how, then, does heterogeneity arise?
Normal Benign
Malignant
Micro-metastatic
Metastatic
Initiation
Promation
Growth Co
Angiogenesis
Intravasation Transport
Conversion
Invasion
Arrest
Colonization Sustained Extravasation growth
METASTASIS
TUMOR PROGRESSION
FIGURE 18-1 TUMOR PROGRESSION
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