Cancer Stem Cells

Biology research studies have discovered that stem cells are critical for the generation of complex multicellular organisms and the development of tumors. To cure a cancer through stable long-term remission, the stem cell compartment of a tumor needs to be eradicated. Stem cells have three distinctive properties:

If normal self-renewal is subverted, it becomes abnormal self-renewal. If increased self-renewal occurs, combined with the intrinsic growth potential of stem cells, it may yield a malignant phenotype. It is possible that cancer stem cells can arise by mutation from normal stem cells or mutated progenitor cells (Fig. 33-2).

Benign tumors are often named by adding the suffix -oma to the cell type (e.g., lipoma), but there are exceptions (e.g., lymphomas, melanomas, hepatomas). Benign tumors arising from glands are called adenomas; those from epithelial surfaces are termed polyps or papillomas.

Benign tumors are characterized by the following:

Other types of tumors include non-neoplastic lesions associated with an overgrowth of tissue that is normally present in the organ (e.g., hyperplastic tissue) and choristomas, normal tissue in a foreign location (e.g., pancreatic tissue in the stomach).

Malignant Tumors

A malignant neoplasm of epithelial origin is referred to as carcinoma, or cancer. Those arising from squamous epithelium (e.g., esophagus, lung) are called squamous cell carcinomas, those arising from glandular epithelium (e.g., stomach, colon, pancreas) are called adenocarcinomas, and those arising from transitional epithelium in the urinary system are called transitional cell carcinomas.

Other types of malignant tumors include amine precursor uptake and decarboxylational tumors. These are neuroendocrine tumors that commonly develop from neural crest and neural ectoderm (e.g., small cell carcinoma of lung). Sarcomas, malignant tumors of connective tissue origin (e.g., fibrosarcoma), and teratomas are derived from all three germ cell layers (e.g., teratoma of the ovary or testis).

Malignant tumors are characterized by the following:

• Increase in the number of cells that accumulate

• Usually, invasion of tissues

• Dissemination by lymphatic spread or by seeding within a body cavity

• Metastasis

• Characteristic nuclear cellular features

• Receptors for integrin molecules (e.g., fibronectin), which help malignant cells adhere to extracellular matrix, type IV collagenases, which dissolve basement membranes, and proteases

• Secretion of transforming growth factor α (TGF-α) and transforming growth factor β (TGF-β) to promote angiogenesis and collagen deposition

• Often, recurrence after attempts to eradicate the tumor by surgery, radiation, or chemotherapy

Biologically distinct and relatively rare populations of tumor-initiating cells have been identified in cancers of the hematopoietic system, brain, and breast. Cells of this type have the capacity for self-renewal, the potential to develop into any cell in the overall tumor population, and the proliferative ability to drive continued expansion of the population of malignant cells. The properties of these tumor-initiating cells closely parallel the three features that define normal stem cells. Malignant cells with these functional properties are termed cancer stem cells (Fig. 33-3). Cancer stem cells can be the source of all the malignant cells in a primary tumor.

Despite decreases in the incidence of some cancers and associated mortality, cancer remains highly lethal and very common. About 41% of Americans will develop some form of cancer, including nonmelanoma skin cancer, in their lifetime; 20% of Americans will die from cancer. Cancer is the second leading cause of death in the United States.

Epidemiology

Lung, colorectal, and breast cancers are the leading causes of cancer deaths in the United States. The types of cancer that have been increasing in incidence are cancer of the lung, breast, prostate, and pancreas and multiple myeloma, malignant melanoma, and Hodgkin’s lymphoma. The types of cancer that are decreasing in incidence are cancer of the stomach, cervix, and endometrium.

Causative Factors in Human Cancer

Factors that cause most neoplasms are unknown. They can be classified as environmental factors (e.g., chemical and radiation), host factors and disease associations, and viruses.

Stages of Carcinogenesis

Some precancerous conditions progress through a series of growth alterations before becoming cancerous. For example, cervical cancer progresses from squamous metaplasia to squamous dysplasia to carcinoma in situ, and finally to invasive cancer. Endometrial cancer progresses from endometrial hyperplasia to atypical endometrial hyperplasia to carcinoma in situ, and finally to invasive cancer.

Cancer (Box 33-1) results from a series of genetic alterations that can include the following:

Mutation or overexpression of oncogenes produces proteins that can stimulate uncontrolled cell growth, whereas mutation or deletion of tumor suppressor genes results in the production of nonfunctional proteins that can no longer control cell proliferation. The mutant cell multiplies and the succeeding generations of cells aggregate to form a malignant tumor.

Interleukin-24 (IL-24), initially called MOB-5, is a protein that is usually secreted by immune system cells in response to injury or infection. Research on colon cancer cells has demonstrated that IL-24, in conjunction with its receptors, appears to give a cancer cell the ability to fuel its own growth. The secreted proteins are released from one cell to transmit a signal to grow, migrate, or survive to another cell. These proteins cannot act alone and must act through a receptor or receptors on the receiving cell.

Cancer-Predisposing Genes

Cancer-predisposing genes may act in the following ways:

Relatively few cancer-predisposing genes have been described. An absence of functional alleles at specific loci, however, allows the genesis of the malignant process (Table 33-3). For example, individuals with certain mutations in the gene BRCA2 are at a very high risk (up to 85%) for developing breast cancer and other cancers (e.g., ovarian cancer) because a DNA repair path cannot properly repair ongoing wear and tear to the DNA.

A mutation in a gene thought to be responsible for colon cancer may initially cause it. This gene, APC, normally limits the expression of a protein, survivin. When APC is altered, survivin works overtime and, instead of dying, stem cells in the colon overpopulate, resulting in cancer. Survivin is overexpressed in colon cancer. It prevents programmed cell death, or apoptosis, the process whereby cells normally die. Rather than dying on schedule, cancer cells instead grow out of control. The APC gene controls the amount of survivin by shutting down its production.

Proto-Oncogenes

Proto-oncogenes act as central regulators of the growth in normal cells that code for proteins involved in growth and repair processes in the body. Proteins such as growth factors or transcription factors are necessary for normal growth.

Genetic mutations in proto-oncogenes produce oncogenes. Oncogene activation causes the overexpression of growth-promoting proteins, resulting in hypercellular proliferation and tumorigenesis. Tumor suppressor genes normally counteract proto-oncogenes by encoding proteins that prevent cellular differentiation. When mutations in tumor suppressor genes cause loss of function, the expressed tumor suppressor proteins are no longer able to suppress cellular growth.

For example, the activation of proto-oncogenes (e.g., ras) involved in the growth process or inactivation of suppressor genes (e.g., p53), which keeps growth in check by binding and activating genes that put the brakes on cell division, is responsible for neoplastic transformation of a cell. Defects in the gene for p53 cause about 50% of all cancers.

Role of Oncogenes

The genetic targets of carcinogens are oncogenes. Oncogenes have been associated with various tumor types (e.g., HER-2/neu with breast, kidney, and ovarian cancers). Oncogenes are considered altered versions of normal genes. Over a lifetime, a variety of mutations can convert a normal gene into a malignant oncogene.

Once an oncogene is activated by mutation, it promotes excessive or inappropriate cell proliferation. Oncogenes have been detected in about 15% to 20% of a variety of human tumors and appear to be responsible for specifying many of the malignant traits of these cells. More than 30 distinct oncogenes, some of which are associated with specific tumor types, have been identified (Table 33-4). Each gene has the ability to evoke many of the phenotypes characteristic of cancer cells.

Major classes of oncogene products involved in the normal growth process of cells include the following:

In addition, tumor suppressor genes (antioncogenes) are guardians of unregulated cell growth (e.g., p53, Rb oncogenes).

Body Defenses Against Cancer

Although there is no single satisfactory explanation for the success of tumors in escaping the immune rejection process, it is believed that early clones of neoplastic cells are eliminated by the immune response. The growth of malignant tumors is primarily determined by the proliferative capacity of the tumor cells and by the ability of these cells to invade host tissues and metastasize to distant sites. It is believed that malignant tumors can evade or overcome the mechanisms of host defenses (Color Plate 18).

Tumor immunity has the following general features:

Host defense mechanisms against tumors are both humoral and cellular. Effector mechanisms include the following:

Tumor Markers

In tumor immunology, a fundamental tenet is that when a normal cell is transformed into a malignant cell, it develops unique antigens not normally present on the mature normal cell. Tumors frequently produce tumor-specific antigens (TSAs) to which the host may develop antibodies. Virus-induced cancers are the most antigenic; chemical-induced cancers are the least antigenic.

Tumor markers are substances present in or produced by tumors that can be used to detect the presence of cancer based on their measurement in blood, body fluids, cells, or tissue (Table 33-5). A tumor marker may be produced by the host in response to a tumor that can be used to differentiate a tumor from normal tissue or to determine the presence of a tumor. Non-neoplastic conditions can also exhibit tumor marker activity (Table 33-6). Some tumor markers are used to screen for cancer, but markers are more often used to monitor recurrence of cancer or determine the degree of tumor burden in the patient. To be of any practical use, the tumor marker must be able to reveal the presence of the tumor while it is still susceptible to destructive treatment by surgical or other means. Tumor markers can be measured quantitatively in tissues and body fluids using biochemical, immunochemical, or molecular tests (Table 33-7).

The search for tumor markers goes back more than 150 years. The earliest identified tumor marker was Bence-Jones protein, a light-chain immunoglobulin, found in patients with multiple myeloma (see Chapter 27). Over the last 15 years, the use of tumor markers in the United States has risen dramatically. Tumor markers play an especially important role in the diagnosis and monitoring of patients with prostate, breast, and bladder cancers.

Older, well-established markers include alkaline phosphatase and collagen-type markers in bone cancer, immunoglobulins in myeloma, catecholamines and their derivatives in neuroblastoma and pheochromocytoma, and serotonin metabolites in carcinoid. In addition, there are many breast tissue prognostic markers (e.g., hormone receptors, cathepsin-D, HER2/neu oncogenes, plasminogen receptors and inhibitors).

The list of tumor markers approved by the U.S. Food and Drug Administration (FDA) continues to grow (Table 33-8). Nine of these biomarkers are protein biomarkers identifiable in blood. Other recently approved protein biomarkers can be detected in urine, such as nuclear matrix protein 22, fibrin and fibrinogen degradation products, and bladder tumor antigen for monitoring bladder cancer, and by immunohistochemical methods using tumor tissues, such as estrogen receptor for breast cancer. Additional FDA-approved cancer biomarkers are DNA-based, such as human epidermal growth factor receptor 2 and HER2/neu for breast cancer, and can be assayed by fluorescent in situ hybridization (FISH). Multiple-marker combinations are useful in the management of some cancers (Table 33-9), but the use of more than two markers is questionable.

An ideal tumor marker would be an assay in which a positive result would only occur in patients with a malignancy, would correlate with stage and response to treatment, and is easily reproducible. No tumor marker to date has met this ideal marker description, nor has any tumor marker has been established as a practical screening test in a general healthy population or in most high-risk populations. The rationale for this poor predictive value of tumor markers is the lack of sensitivity and specificity in the low cancer rates that prevail in population groups. Because of the low prevalence of cancer, in general, even assays that are highly sensitive and specific may have a low predictive value.

DNA Microarray Technology

New developments in molecular genetics involve DNA microarray technology (see Chapter 14). Cancer can arise not only from mutations in oncogenes and tumor suppressor genes, but also from genes involved in cell cycle control, DNA repair, and apoptosis. Microarrays have the potential to uncover signature gene expression patterns for specific cancers and ultimately assist in the staging of tumors, prognosis, and treatment. Microarrays may help disclose global gene expression pattern differences between healthy and diseased cells as more sensitive and specific diagnostic markers are developed, such as CD44+/CD24− gene expression profile in breast cancer versus normal breast tissue. When differentially expressed genes were used to generate a 186-gene invasiveness gene signature (IGS), the IGS was strongly associated with metastasis-free survival and overall survival for four different types of tumors.

Proteomic technology uses two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry. Although these techniques are not revolutionary, advances have improved their sensitivity. Expansion of computer-assisted bioinformatics has simplified the process of protein identification from mass spectra. Mass spectra are proving to be comparable to CA 125 for the detection of early-stage ovarian cancer.

In colorectal cancer, fecal DNA screening has been demonstrated to be useful. Oncogene mutations that characterize colorectal neoplasia are detectable in exfoliated epithelial cells in the stool. Neoplastic bleeding is intermittent but epithelial shedding is continual, potentially making fecal DNA testing more sensitive.

Next Generation Sequencing (NGS) as described in Chapter 14, Molecular Techniques, is another step toward personalized cancer treatment. Three aspects of importance in NGS are:

Modalities For Treating Cancer

Many different modes of therapy, including angiogenesis inhibitors, which keep tumors from building new blood vessels to supply themselves with food and oxygen, have demonstrated effectiveness in the treatment of cancer (Table 33-10).

The test is a chromatographic immunoassay (CIA) for the rapid semi-quantitative determination of PSA in body fluids. It contains two monoclonal murine anti-PSA antibodies as active compounds. One of these antibodies is immobilized at the test region on the membrane. A glass fiber pad downstream of the membrane is used for sample loading and transmission to a second fiber pad with the dried and gold labeled second monoclonal murine anti-PSA antibody. PSA at the sample will bind to the remobilized gold-labeled antibody and form a PSA-gold-labeled-anti-PSA-antibody-complex. The colored gold labeled anti-PSA-antibody will bind to the anti-mouse antibody at the control region and the region of the internal standard thus developing two red lines (one at the control region and one at the region of the internal standard). If the sample contains PSA, the PSA-gold-labeled anti-PSA-antibody complex will bind to the immobilized monoclonal antibody of the test result region that recognizes another epitope on the PSA molecule (sandwich complex). The binding is indicated by the formation of an additional line.

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