The Nature of Cancer

By E. Loren Buhle, Jr. Ph.D.

It is estimated that cancer affects three out of four families in the United States. The disease and, often, it treatments cause substantial mortality and morbidity, prompting intense interest in the exact changes that cells undergo as they become malignant. Scientists are also interested in factors causing clinical disease. Once the course of carcinogenesis and patterns of disease progression are identified, actions can be taken to eliminate or lessen the risk of cancer.

 

Characteristics of Malignant Cells

Normal cells reproduce in an orderly, controlled fashion. In some body tissues, such as the epidermis (e.g. skin), the bone marrow (where the blood is made), and the mucous membranes, new cells are formed regularly in order to compensate for the high loss from injury. Some cells, such as neurons, do not have the ability to reproduce and cannot regenerate even after tissue damage.

Normally, new cells are divide at a controlled rate, keeping the overall number of cells nearly constant. Feedback mechanisms that stimulate or inhibit cell division regulate the growth of normal cells. In contrast, the body's normal regulatory mechanisms are usually unable to control the proliferation of cancer cells once malignant transformation has taken place. Cancer cells may also lose the ability to differentiate.

Differentiation is the process by which normal cells undergo physical and structural changes as they develop to form different tissues of the body. Differentiated cells specialize in different physiological functions. For example, a highly differentiated cell like a nerve cell still shares many features in common all cells (i.e. nucleus, cell membrane, and mitochondria). However, microscopically and functionally they are unique from other cell types in the body.

The degree of differentiation of malignant cells is variable. Cancer cells that closely resemble the tissue of origin are called well-differentiated, while bizarre tumor cells bearing little similarity to the tissue of origin are termed undifferentiated or anaplastic. Undifferentiated or anaplastic malignancies are usually more aggressive in their growth and behavior than well-differentiated types. There are also intermediate degrees of differentiation. These tumors are classified as moderately differentiated.

Although malignant cells frequently lose their function, appearance, and properties associated with the normal cells of the tissue of origin, in some cases they can acquire new cellular functions uncharacteristic of the originating tissue. For example, tumors in the non-endocrine tissues sometimes acquire the ability to produce and secrete hormones or other proteins. Small-cell lung cancer is an example of a hormone secreting tumor, which may produce adrenocorticotropic hormone (ACTH) in amounts sufficient to cause Cushing's syndrome. The ovarian endodermal sinus tumor characteristically produces alpha-feto protein (AFP). AFP is a protein that is normally produced during fetal life. It is however re expressed by these tumors.

Tumor simply means abnormal growth. Frequently this term is incorrectly used interchangeably with cancer. However, tumor may refer to a benign or malignant growth. Both benign and malignant tumors result from abnormal proliferation of cells. Unlike malignant cells, benign tumor cells tend to retain their similarity to the tissue of origin (i.e. they remain differentiated). More importantly, in benign growths

1. the cells do NOT invade the surrounding tissue, and
2. the cells do NOT break away and travel to distant sites and proliferate in the abnormal site (metastasis).

Benign tumors are generally associated with a more favorable prognosis, unless their presence causes pressure in critical areas such as the brain. The following table outlines the differences between benign and malignant tumors.

Benign	Malignant
Encapsulated Noninvasive Highly differentiated Mitoses rare Slow growth Little or no anaplasia No metastases	Nonencapsulated Invasive Tendency toward de-differentiation Mitoses may be relatively common Usually rapid growth Anaplastic to varying degrees May Metastasize

Carcinogenesis

Carcinogenesis is the process by which a normal cell undergoes malignant transformation. It is generally accepted that malignant transformation is a multi-step process.

It involves multiple, cumulative alterations to the cell's DNA leading to genetic damage. Many scientists now consider cancer to be a "disease of the genes". The "multiple-hit hypothesis" states that several individual sites of genetic damage (i.e. "hits") are required to transform a cell the malignant phenotype. When once the cell has become transformed, it will usually divide with normal cell-cycle control mechanisms and thereby divide many times forming a malignant "clone" of cells. Most human tumors are monoclonal. Monoclonal means that all of the cells in that patient's malignant tumor contain the same pattern of genetic damage that led to transformation. Unfortunately, one patient's tumor may (and in probably does) contain a different set of genetic "hits" that led to the transformation to the malignant phenotype.

Carcinogens are agents capable of initiating carcinogenesis. Environmental, genetic and viral factors have been implicated as carcinogens.

 

Categories of Known and Suspected Factors in Carcinogenesis
Environmental Factors	Chemical carcinogens hydrocarbons coal tars tobacco smoke industrial factors asbestos medications hormones cytotoxic drugs Dietary Factors obesity alcoholism Radiation ultraviolet ionizing
Genetic (hereditary) Factors
Viruses	human papilloma virus (HPV) Herpes Simplex virus (HSV) Hepatitis
Spontaneous mitotic defects
Immune deficiency

 

The role of oncogenes and tumor suppressor genes in tumor initiation are the current focus of many investigators. Oncogenes are genes within the cell that may initiate the cell's transformation from normal to malignant. Interestingly, examples of positively acting oncogenes are quite rare in human tumors. So-called tumor suppressor genes probably play a more important role. Well known tumor suppressor gene include the P53 gene and the retinoblastoma gene (Rb). These genes are involved in controlling the cell-cycle. It is believed that p53 acts by sensing DNA damage within the cell and preventing the cell from replicating until the DNA damage is repaired by intrinsic mechanisms. If the damage is able to be repaired, p53 allows the cell to divide. This action prevents cells with DNA damage from dividing and therefore, suppresses potential tumors. If the DNA damage is to extensive, p53 causes commits the cell to die without dividing. This programmed cell death is called apoptosis. However, if a mutation occurs in the P53 gene, then its function may be impaired and cells with genetic damage may replicate and malignant transformation may occur.

P53 is a well characterized example of a tumor suppressor gene. It is likely that many new tumor suppressor genes that are intimately involved with controlling the cell-cycle will be discovered over the next few years.

Note: P53 is the gene coding for the p53 protein. The capital "P" refers to the gene, while the lowercase "p" refers to the gene product or protein.

 

Disease Process

Cancers cause morbidity through local growth, metastasis to distant organs, and systemic effects of the disease. Malignant tumors can grow large enough at the primary site to interfere with function at the involved organ or to compress nearby organs and structures. Ovarian tumors frequently shed cells into the peritoneal cavity, where they grow to cover the surface of the abdominal organs. This intraabdominal growth may cause bowel or ureteral obstruction. Cancer can also spread to adjacent structures and penetrate body cavities by direct extension.

Malignant tumors differ from the benign ones in their ability to metastasize, or spread from the primary site to other locations in the body. Metastasis occurs when cells break away from the primary tumor, travel through the body via the blood and/or lymphatic circulation, and become trapped in the capillaries of organs. From there, they proliferate and infiltrate the organ tissue and grow into new tumor deposits.

Patterns of metastasis differ from one cancer to another. Cancers tend to metastasize to specific organs or sites in the body. Clinical symptoms and problems vary according to the organ involved and the extent of disease. A brief overview of the primary disease and the likely sites of metastatic spread are presented here.

In addition to the local effects of tumor growth, cancer can produce systemic signs and symptoms that are not direct effects of either the tumor or its metastases. These manifestations are collectively referred to as paraneoplastic syndromes. Many of these syndromes involved ectopic hormone production by tumor cells or the secretion of biochemically active substances that cause metabolic abnormalities. Paraneoplastic syndromes can also involve the nervous, hematological, renal, gynecologic and gastrointestinal systems.

 

Staging

Staging is the process of describing the extent of disease at the time of diagnosis in order assess prognosis and to aid in treatment planning, and compare different treatment approaches. The TNM classification proposed by the American Joint Commission on Cancer is the most frequently use system for defining the extent of disease. The T refers to the anatomical size of the primary tumor; N is the extent of lymph node involvement; and M denotes the presence or absence of metastases. An example is given for breast cancer.

 

Classification of Tumors

Cancers are named according to the site of the primary tumor and the type of tissue involved (histology). The three major classifications of normal body tissue are epithelial, connective and muscle, and nerve tissue.

Epithelial tissues cover all external body surfaces and line all internal spaces and cavities. The skin, mucous membranes, gastrointestinal tract, and the lining of the bladder are examples of epithelial tissues. The functions of epithelial tissues are to protect, excrete, and absorb. Cancer originating in the epithelial tissue is called a carcinoma.

Connective tissue consists of elastic, fibrous, and collagenous tissues, such as bone, cartilage, and fat. The function of such tissue is to connect, support, and protect. Cancers originating in connective tissue and in muscle are called sarcomas.

Nerve tissue includes the brain, spinal cord, and nerves. It consists of two types of cells: neurons and glial cells. Tumors arising in nerve tissue do not have a common name, but are named specifically for the type of cell involved. For example, tumors arising from astrocytes, a type of glial cell thought to form the blood-brain barrier, are called astrocytomas. Tumors arising in nerve tissue are often benign, but, because of their critical location, are more likely to be harmful than benign tumors in other sites. Below is a list of benign and malignant tumors according to their tissue of origin.

 

Classification of Tumors

Tissue of Origin	Benign Tumor	Malignant Tumor
Epithelial
surface epithelium epithelial lining of glands or ducts	papilloma adenoma	carcinoma adenocarcinoma
Connective Tissue and Muscle
fibrous tissue cartilage bone smooth muscle striated muscle	fibroma chondroma osteoma leiomyoma rhabdomyoma	fibrosarcoma chondrosarcoma osteosarcoma leiomyosarcoma rhabdomyosarcoma
Nerve tissue
glial meninges retina	meningioma	glioma meningeal sarcoma retinoblastoma

---

A tumor's histologic type is determined by the appearance and organization of the cells when examined under a microscope. In many parts of the body, more than one type of tissue may be involved, and cancers of more than one histologic type can develop. Thus, cancer arising from the glandular tissue of the prostate gland is classified as an "adenocarcinoma" of the prostate, while a tumor arising from the striated muscle in the prostate will be termed a "rhabdomyosarcoma" of the prostate. It is important to determine the cancer's histologic type, because this affects decisions about treatment approaches and estimates of prognosis.

 

Common Sites of Disease

Primary Disease

Bone

Marrow

Skin

Lung

Liver

Bowel or rectum

Nodes

Spleen

Kidney

Brain

Serosa

Other pelvic organs

Meninges

Adrenal Glands

Bladder

.

.

.

.

.

.

X

.

X

.

.

X

.

.

Brain

.

.

.

.

.

.

.

.

.

.

.

.

X

.

Breast

X

.

.

X

X

.

X

.

.

X

.

.

X

.

Cervix

X

.

.

X

X

X

X

.

X

.

.

.

.

.

Colon

.

.

.

X

X

.

X

.

.

.

.

.

.

.

Esophagus

X

.

.

X

X

.

X

.

.

.

.

.

.

.

Head/Neck

.

.

X

X

.

.

X

.

.

.

.

.

.

.

Hepatoma

X

.

.

X

.

.

X

.

.

.

.

.

.

.

Kidney

X

.

.

X

X

.

X

.

.

X

.

.

.

.

Lung

X

X

.

.

X

.

X

.

X

X

.

.

X

.

Melanoma

X

.

X

X

X

.

X

.

.

X

.

.

.

.

Mycosis Funoides

X

X

.

.

.

.

X

X

.

.

.

.

.

.

Ovary

.

.

.

X

X

X

X

.

.

.

X

.

.

.

Pancreas

.

.

.

X

X

X

X

.

.

.

.

.

.

.

Prostate

X

.

.

X

X

.

X

.

.

.

.

.

.

.

Sarcoma

.

.

.

X

.

.

X

.

.

.

.

.

.

.

Stomach

X

.

.

X

X

.

X

.

.

.

.

.

.

.

Testes

X

.

.

X

X

.

X

.

.

.

.

.

.

.

Thyroid

X

.

.

X

.

.

X

.

.

.

.

.

.

.

Uterus

.

.

.

X

.

.

.

.

.

.

.

X

.

.

 

 

Conclusion

Each type of cancer expresses characteristics peculiar to itself, but all probably share the same basic nature and process of development. It is now becoming apparent that cancer is indeed a "disease of the genes." By understanding the process of carcinogenesis at the molecular level and identifying intrinsic and extrinsic factors that affect that process, we may learn how cancer can be prevented and how to effectively treat clinically expressed cancers.