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SYMPOSIUM: BIOLOGY OF CANCER

1. INTRODUCTION

FUNDAMENTALS AND TERMINOLOGY

If the normal stability of the organization of tissues and organs is disturbed, a variety of disease states can occur. One example is a tissue in which the control of growth becomes defective, called a "tumor" or "neoplasm" (literally "new growth"). Neoplasms can be classified as benign or malignant, and the common term for the malignant tumor is cancer. The word cancer is taken from the Latin term for "crab" because early physicians noticed that certain skin cancers had a crablike appearance.

In almost every case, malignant tumors are "monoclonal", meaning that they develop from a single cell. The progenitor cell has undergone a permanent, heritable change that is transmitted to all its progeny, a process called the "neoplastic transformation". Clinically, the distinction between benign and malignant is based on the effect of the neoplasm on the survival of the host organism: The host can die from the effects of the malignant tumor but will survive the presence of the benign tumor.

At the cellular level, the most important difference is the likelihood that the tumor will spread. Benign tumors typically are encapsulated nodules of neoplastic tissue and therefore do not spread, whereas malignant tumors often spread to neighboring tissues and even other parts of the body. This spread to neighboring tissues is called "invasion"; the spreading to distant organs is called "metastasis", and the tumor nodules resident at sites distant from the parent tumor are referred to as metastases...

Tumors may arise from mature, differentiated cells or from mitotically active stem cell populations. Stem cells are relatively undifferentiated, mitotically active cells from which some more highly differentiated cells "stem". An example is the mitotically active hematopoietic ("blood-forming") stem cell population found in bone marrow that gives rise to red and white blood cells. The stem cells of various tissues are often designated by the suffix "-blasts". For example, neuroblasts are the mitotic stem cells for neurons; myoblasts are the stem cells for myocytes; and fibroblasts are the stem cells for fibrocyte connective tissue cells. Cancers of a stem cell may be designated by the suffix "-omas": neuroblastomas for tumors of neuroblastic origin; myelomas for tumors of myeloblasts, which are the stem cells of the granular leukocytes (white blood cells).

Another important element in tumor categorization is the tissue class of origin. "Carcinoma" refers to a tumor derived from an epithelial tissue, and "sarcoma" refers to a tumor derived from connective tissue. As indicated above, the hematopoietic system includes stem cell populations that grow and divide throughout life. All of these populations are subject to neoplasia: "lymphomas" are tumors of the lymphocytic lineage, "leukemias" and "myelomas" are tumors of the leukocytic system (the granulocytes, eosinophils, and basophils), and "erythroblastomas" are tumors of the red cell lineage.

Adapted from: W.M. Becker and D.W. Deamer (eds.): The World of the Cell. 2nd Edition. Benjamin/Cummings 1991. p.718.

SOME OF THE MAIN TYPES OF CANCER

Carcinomas (approximately 90% of all cancers):

Skin: Basal cell carcinoma, Squamous cell carcinoma

Lung: Pulmonary adenocarcinoma

Breast: Mammary adenocarcinoma

Stomach: Gastric adenocarcinoma

Colon: Colon adenocarcinoma

Uterus: Uterine endometrial carcinoma

Prostate: Prostatic adenocarcinoma

Ovary: Ovarian adenocarcinoma

Pancreas: Pancreatic adenocarcinoma

Urinary bladder: Urinary bladder adenocarcinoma

Liver: Hepatocarcinoma

Sarcomas (approximately 5% of all cancers):

Bone: Osteosarcoma

Cartilage: Chondrosarcoma

Fat: Liposarcoma

Smooth muscle: Leiomyosarcoma

Skeletal muscle: Rhabdomyosarcoma

Connective tissue: Fibrosarcoma

Blood vessels: Hemangiosarcoma

Nerve sheath: Neurogenic sarcoma

Meninges: Meningiosarcoma


Lymphomas/Leukemias (approximately 5% of all cancers):

Red blood cells: Erythrocytic leukemia

Bone marrow cells: Myeloma or

myelocytic leukemia

White blood cells: Lymphoma or

lymphocytic leukemia


Adapted from: L. Kleinsmith and V. Kish: Principles of Cell and Molecular Biology. HarperCollins 1995, p.780.

CELL REGULATION, ONCOGENES, AND VIRUSES

"The generation of a differentiated cell from its ultimate ancestor -- a stem cell -- is a complex process involving the selective switching on and off of specific developmental genes. This switching requires cell division, which itself is controlled by a complex set of genes whose activity is highly regulated. Eventually the differentiated cell will have established subtle interactions between itself and other cells in the differentiated tissue in which it resides. Further, many differentiated cells will be responsive to specific chemokines so that cell replication and differentiated function can be initiated under appropriate conditions. Errors in this process can lead to nonfunctional cells. More dangerously for the organism, however, many errors in differentiation can lead to cells that do not respond properly to environmental and functional signals. These include signals to cease replication when optimal cell density in a tissue has been reached and to cease or modulate the expression of chemokines that influence the activity and growth of other tissue. Some cells that experience this type of damage can ultimately become cancer cells if they continue to accumulate damage to normal regulatory processes.

"There are a number of genetic control points that can assess the health and appropriateness of the metabolic processes of the differentiated cell. First, the cell contains many genes directly involved in growth control; these are often termed 'oncogenes' because of their role in oncogenesis. Oncogenes can be either dominant or recessive depending on their function. Dominant ones involve the action of a protein or enzyme to ensure that cell division only takes place in response to a set of highly regulated extracellular and intracellular signals. Recessive oncogenes function to shut down cellular division; the Rb and p53 tumor suppressor are the best-characterized examples.

"Numerous other control points in the cell and in the animal also survey individual cells to determine whether they are actually or potentially damaged in their ability to control their replication and function. These include the numerous pathways of programmed cell death (apoptosis) that exist in cells when replication has occurred inappropriately or too often. Cells of the immune system including natural killer (NK) and specific cytotoxic T cells are available to destroy cells whose growth properties are abnormal. Finally, interferon-gamma has antitumor activity that serves to modulate or control cell proliferation.

"These control points must be abrogated for cancer to develop, and the complex and manifold nature of the controls is the basic reason why carcinogenesis is a multistep and random process associated with genetic damage. Still, like all journeys, carcinogenesis must begin with a single step, and this step is often the specific interruption of one or another control point leading to cells that are susceptible to accumulating further genetic damage... Many of these changes can be assayed in cultured cells, and the study of the alteration of growth properties of cultured cells provides an important experimental model for the study of carcinogenesis.

"Many groups of viruses induce specific alterations in the control of cell division and cell mortality, and their study has allowed the identification of many factors involved in carcinogenesis. It is true that some (even many) of the viruses classified as tumor viruses act as such only in laboratory settings. Also, it is true that only a few human cancers are consistently associated with virus infections, and then only after long periods of virus-host interaction. Still, there is no gainsaying the fact that the study of tumor viruses has provided the major impetus to our understanding of the process of tumor formation, and through this, how to control and ultimately cure certain types of cancers."

E. Wagner and M. Hewlett: Basic Virology. Blackwell Science 1999. p.398.

ON METASTASIS IN CANCER

J.E. Gershenwald and I.J. Fidler (University of Texas, US) discuss metastasis in cancer, the authors making the following points:

1) The major cause of death from cancer is dissemination of the primary tumor, leading to formation of metastases that are resistant to conventional chemotherapy. Several factors account for the failure to treat metastases. First, neoplasms are biologically heterogeneous and contain subpopulations of cells with different angiogenic, invasive, and metastatic properties. Second, the process of metastasis selects for a small subpopulation of cells that preexist within a parental neoplasm. Third, and perhaps the greatest obstacle for therapy, is that the outcome of metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that the tumor cells usurp (1). A better understanding of the molecular events that lead to metastasis and of the complex interactions between metastatic cells and host factors is essential for the design of more effective cancer therapies.(2)

2) To produce a metastasis, tumor cells must complete a series of sequential, interrelated steps. These include growth; neovascularization and lymphangiogenesis (development of new lymphatic vessels); invasion of the host stroma, blood vessels, and lymphatic system; survival in the circulation; arrest in small blood vessels; extravasation (migration out of blood vessels) into the parenchyma of organs; and continuous proliferation, which depends on establishing an adequate blood supply (angiogenesis) (1). Early clinical observations suggested that solid tumors (carcinomas) spread primarily via the lymphatic vessels and that mesenchymal (connective tissue) tumors spread mainly through the bloodstream. In truth, the lymphatic and vascular systems have numerous connections that allow disseminating tumor cells to pass rapidly from one system to the other (3).

3) Although the importance of the lymphatic system has been recognized for centuries (4), its involvement in the metastatic cascade has taken a back seat to the recent explosive interest surrounding the formation of tumor-associated blood vessels. Fortunately, recent work is beginning to elucidate the molecular mechanisms of lymphangiogenesis and lymphatic metastases. Among the unresolved controversies is the question of whether cancer cells in a primary tumor are transported to regional lymph nodes through intratumor lymphatic vessels. New techniques, such as intradermal administration of vital blue dye and radiolabeled colloid at the periphery of primary tumors, can identify the specific lymph nodes that receive afferent lymphatic drainage from the primary tumor site. These sentinel lymph nodes are the most likely to contain tumor metastases, which are often harbingers of future tumor development at sites distant from the lymph node (5).

References (abridged):

1. J. Fidler, in Clinical Oncology, M. D. Abeloff, J. O. Armitage, A. S. Lichter, J. E. Niederhuber, Eds. (Churchill Livingstone, New York, ed 2, 2000), pp. 29-53

2. T. P. Padera et al., Science 296, 1883 (2002).

3. Carr, Cancer Metastasis Rev. 2, 307 (1983)

4. R. S. Foster Jr., Surg. Oncol. Clin. N. Am. 5, 1 (1996)

5. J. E. Gershenwald et al., J. Clin. Oncol. 17, 976 (1999)

Science 2002 296:1811

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