BIOLOGY, CLINICAL MANIFESTATIONS, AND TREATMENT OF CANCER

The most generally accepted definition of a tumor is that it is a tissue overgrowth which is independent of the laws governing the remainder of the body. It is usual to add as a qualifying phrase to separate tumors from reparative processes, such as bone callus, that the neoplasm overgrowth serves no useful purpose to the organism.¹

Tumor Classification and Nomenclature

Proper identification of a cancer is important for many reasons. Different lesions will have different causes, different rates and patterns of progression, and different responses to treatment. Cancer classification starts with knowing the site of origin and microscopic appearance of the lesion, but can extend to a detailed description of critical genetic changes in the cancer.

Benign tumors, which are not referred to as cancers, are usually encapsulated and well differentiated. They retain some normal tissue structure and do not invade the capsules surrounding them or spread to regional lymph nodes or distant locations. Benign tumors are generally named according to the tissues from which they arise, and include the suffix “-oma.” For example, a benign tumor of the smooth muscle of the uterus is a leiomyoma, and a benign tumor of fat cells is a lipoma.

Some tumors initially described as benign can progress to cancer and then are referred to as malignant tumors. These tumors are distinguished from benign tumors by their more rapid growth rates and specific microscopic alterations, including loss of differentiation and absence of normal tissue organization. One of the hallmarks of cancer cells, as seen under the microscope, is anaplasia, the loss of cellular differentiation, irregularities of the size and shape of the nucleus, and loss of normal tissue structure. Malignant tumors lack a capsule and grow to invade nearby blood vessels, lymphatics, and surrounding structures. The most important and most deadly characteristic of malignant tumors is their ability to spread far beyond the tissue of origin, a process known as metastasis (Figures 11-1 and 11-2; see Table 11-1).

In general, cancers are named according to the cell type from which they originate. Cancers arising in epithelial tissue are called carcinomas, and if they arise from or form ductal or glandular structures are named adenocarcinomas. Hence, a malignant tumor arising from breast glandular tissue is a mammary adenocarcinoma. Cancers arising from connective tissue usually have the suffix sarcoma. For example, malignant cancers of skeletal muscle are known as rhabdomyosarcomas. Cancers of lymphatic tissue are called lymphomas, whereas cancers of blood-forming cells are called leukemias. However, many cancers, such as Hodgkin disease and Ewing sarcoma, are named for historical reasons that do not follow this naming convention. Table 11-2 presents the nomenclature and classification of selected tumors.

The Biology of Cancer Cells

Tumor Markers

Tumor markers (biologic markers) are substances produced by cancer cells that are found either in or on the tumor cells or in the blood, spinal fluid, or urine (Table 11-3). Some tumor markers have been known for many decades. For diseases associated with a tumor marker, there is indeed a “blood test for cancer.” Tumor markers include hormones, enzymes, genes, antigens, and antibodies. For example, the adrenal medulla normally secretes the catecholamine epinephrine (adrenaline). Benign tumors of the adrenal medulla can produce catecholamines in vast excess, leading to rapid pulse, high blood pressure, sweats, and tremors. Elevated blood or urine levels of catecholamines in someone with this set of symptoms strongly suggest the presence of an adrenal medullary tumor (pheochromocytoma). Liver and germ cell tumors secrete a protein known as alpha fetoprotein (AFP) into the blood, and prostate tumors secrete prostate specific antigen (PSA) into the blood. These tumor markers can be used in three ways: (1) to screen and identify individuals at high risk for cancer; (2) to help diagnose the specific type of tumor in individuals with clinical manifestations relating to cancer, as in adrenal tumors; and (3) to follow the clinical course of cancer. For example, a falling PSA after therapy for prostate cancer indicates successful treatment, and a later rise in the PSA may indicate a recurrence.

A significant problem in diagnosing cancer using tumor marker assays is that nonmalignant conditions also can produce tumor markers. The presence of an elevated tumor marker therefore may suggest a specific diagnosis, but it is not used alone as a definitive diagnostic test. Identification of ideal sensitive and specific tumor markers that are elevated early in the course of common cancers remains a high priority because the early detection of cancer often improves the treatment outcome.

Cancer-Causing Mutations in Genes

Prior to the advent of modern molecular biology, many different causes of cancer were postulated, based on epidemiologic studies, studies of carcinogens, and studies of viruses. We now understand that changes in the genes of the cancer cell cause the cell to become cancerous. As our knowledge of cancer biology continues to increase so too does our understanding of the many ways that heritable changes in cells can contribute to cancer. These changes include deoxyribonucleic acid (DNA) mutations, but also include changes in DNA and histone chemical modification (epigenetic changes), and, most recently recognized, changes in micro-ribonucleic acid (miRNA) expression (also see Chapters 4 and 12). Although the word mutation is used extensively here, it can also refer to heritable changes in gene expression (epigenetics) that do not involve changes in DNA sequence.

Cancer is predominantly a disease of aging. Perhaps the most telling epidemiologic data are presented in Figure 11-8. The incidence of cancer, that is, the fraction of individuals in each age group who develop cancer, increases dramatically with age. The best explanation for this epidemiologic data is that each individual acquires a number of genetic “hits” or mutations over time. When sufficient mutations have occurred, cancer develops. These epidemiologic data agree well with observation of mutations in early and advanced cancers and from experimental cancers created in the laboratory—four to seven specific hits are required to cause a full-blown cancer.⁹

Types of Genes Misregulated in Cancer

Oncogenes and Tumor-Suppressor Genes: Accelerators and Brakes

The previous discussion refers to the activating and inactivating of various genes as being key in the development of cancer. Just what types of changes in genes actually occur in cancer? First, it is useful to distinguish between oncogenes and tumor-suppressor genes. Table 11-4 compares the two types of cancer genes. Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate (accelerate) proliferation. Conversely, tumor-suppressor genes encode proteins that in their normal state negatively regulate (halt, or “put the brakes on”) proliferation. Hence, they also have been referred to as anti-oncogenes.

In its normal, nonmutant state, an oncogene is referred to as a proto-oncogene. An example of a proto-oncogene would be a growth factor (e.g., epidermal growth factor), or a growth factor receptor (e.g., epidermal growth factor receptor). Other positive regulators of proliferation are in the signal transduction pathway that transmits the signal from the growth factor receptor to the cell nucleus. Normally, ras is a proto-oncogene (see Figure 11-11).

Guardians of the Genome

The previous discussion of mutations leads naturally to the question of how mutations occur in the first place. The integrity of genetic information can be compromised at several points: during each round of DNA synthesis, during each mitosis when chromosomes are segregated to daughter cells, and when external mutagens (e.g., chemicals and radiation) alter or disrupt DNA. Multiple mechanisms have evolved to protect and repair the genome.³¹ These repair mechanisms are directed by caretaker genes, genes that are responsible for the maintenance of genomic integrity. Caretaker genes encode proteins that are involved in repairing damaged DNA, such as occurs with errors in DNA replication, mutations caused by ultraviolet or ionizing radiation, and mutations caused by chemicals and drugs. Loss of function of caretaker genes leads to increased mutation rates. If DNA damage is severe, the cell undergoes programmed cell death, or apoptosis, rather than simply dividing with damaged DNA.

Inherited mutations can disrupt the caretaker genes that protect the integrity of the genome. Examples include the disorder xeroderma pigmentosum (XP); affected individuals have defects in the repair of ultraviolet light–induced DNA damage and should avoid direct sunlight exposure. They have a very high incidence of skin cancer. Hereditary nonpolyposis colorectal cancer (HNPCC) results from an inherited defect in repairing DNA base pair mismatches that occur from time to time during DNA replication. Affected individuals have an increased rate of small insertions and deletions in DNA, leading to a high rate of colon and other cancers.³² Finally, there are inherited mutations that threaten the integrity of entire chromosomes. Bloom syndrome and Fanconi aplastic anemia are two autosomal recessive disorders in which affected individuals demonstrate marked chromosomal instability. Chromosome breaks, aberrant fusions, and chromosome loss are common. As a consequence, these individuals have a high risk of developing cancer at an early age.

The rate of individual gene mutation is probably too low to account for the acquisition of many new mutations during the evolution of a malignant cancer clone. In addition to abnormal epigenetic silencing, chromosome instability (often referred to as CIN) also appears to be increased in malignant cells.³³ The underlying mechanism of this instability is not clear but may be caused by malfunctions in the cellular machinery that regulates chromosome segregation at mitosis.³⁴ Chromosome instability results in a high rate of chromosome loss, as well as loss of heterozygosity and chromosome amplification. Each of these events can accelerate the loss of tumor-suppressor genes and the overexpression of oncogenes.

Inflammation, Immunity, and Cancer

Chronic inflammation has been recognized for close to 150 years as being an important factor in the development of cancer.^37,38 Epidemiologic studies strongly support the conclusion that the active immune response in chronic inflammation predisposes to cancer. Individuals who have suffered with ulcerative colitis for 10 years or more have up to a 30-fold increase in the risk of developing colon cancer. Chronic viral hepatitis caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection markedly increases the risk of liver cancer. A large study found a 66% increase in risk of lung cancer among women with chronic asthma, an inflammatory disease of the airways.³⁹ Table 11-6 details the various inflammatory conditions and infectious agents associated with cancer.

The reasons for the association of inflammation and cancer are complex and differ from site to site. After injury and during infection, inflammatory cells, including neutrophils, lymphocytes, and macrophages release cytokines and growth and survival factors that stimulate local cell proliferation and new blood vessel growth to promote wound healing by tissue remodeling (see Chapter 6). These factors combine in chronic inflammation to promote continued proliferation (Figures 11-19 and 11-20). In addition, inflammatory cells release compounds such as reactive oxygen species (ROS), and other reactive molecules that can promote mutations and block the cellular response to DNA damage. Notably, increased abundance of the enzyme cyclooxygenase-2 (COX-2), which generates prostaglandins during acute inflammation, has been associated with colon and some other cancers. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin. that inhibit COX-2 can reduce the risk of colon cancer by as much as 20% (see Chapter 5).⁴⁰

The Immune System Protects Us Against Viral-Associated Cancers

It is a popular belief that damage to the immune system may lead to development of common cancers. This idea arose decades ago as our understanding of the immune response against infectious disease developed. Modern data support a more nuanced conclusion. Although the immune system is indeed important in protecting us against cancers caused by specific viral infections (detailed later), it does not effectively protect us against most common cancers. Individuals on chronic powerful immunosuppressive drugs, such as those given for kidney, heart, or liver transplant, have a much higher risk of developing viral-associated cancers, with a 10-fold increased risk of non-Hodgkin lymphoma (caused by Epstein-Barr virus) and up to 1000-fold increased risk of developing Kaposi sarcoma (caused by human herpesvirus 8 [HHV8]) (additional information about viruses and cancer below.) The same immunosuppressed individuals, however, have only a slight increase in the risk of common cancers such as lung and colon cancer (and this could well be because of increased inflammation at those sites) and no increase in the risk of breast or prostate cancer.^41,42

In fact, there are many complex interactions between elements of the immune system and tumors (Figure 11-20). Tumors activate surrounding stromal and inflammatory cells, including tumor-infiltrating lymphocytes and macrophages, to secrete multiple cytokines that support tumor growth and spread. In parallel, various cells of the immune system can exert antitumor effects through factors such as TNF-related apoptosis-inducing ligand (TRAIL), interleukin (IL)-10 and IL-12. The double-edged effects of the immune cells, both promoting and inhibiting proliferation, may explain why it has been so difficult to harness the immune system to fight cancer.

Viral Causes of Cancer

As noted, a number of viruses have been associated with human cancer^43,44 (Table 11-7). An even broader spectrum of viruses have been associated with cancer in animals. In humans, hepatitis B and C viruses (HBV, HCV), Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) (also known as HHV8), and human papillomavirus (HPV) are associated with about 15% of all human cancers worldwide. Cancer of the cervix and hepatocellular carcinoma account for about 80% of virus-linked cancer. The initial infection with hepatitis B or C is not associated with cancer; instead, it is acquisition of a chronic viral hepatitis that markedly increases cancer risk (also see Inflammation, Immunity and Cancer). Chronic hepatitis B infections are common in parts of Asia and Sub-Saharan Africa and confer up to a 200-fold increased risk of developing liver cancer. Chronic hepatitis C infections have become increasingly recognized in Western countries. Up to 80% of liver cancer worldwide is associated with chronic hepatitis caused either by HBV or HCV. In both cases, it appears that a lifetime of chronic liver inflammation predisposes to the development of hepatocellular carcinoma. Widespread use of the HBV vaccine is expected to significantly decrease the incidence of chronic hepatitis B and hence hepatocellular carcinoma. Unfortunately, a vaccine for HCV is not yet available.

Virtually all cervical cancer is caused by infection with specific subtypes of HPV, which infects basal skin cells and commonly causes warts. There are more than 100 HPV subtypes, but only a few (HPV16, 18, 31, 45, and a few others) are associated with cervical, anogenital, and penile cancer (see Chapters 12 and 23). HPV causes cancer when the viral DNA becomes accidentally integrated into the genomic DNA of the infected basal cell of the cervix and directs the persistent production of viral oncogenes. Early oncogenic HPV infection is readily detected by the Papanicolaou (Pap) test, an examination of cervical epithelia scrapings. Early detection of cellular atypia in a Pap test alerts healthcare providers to the possibility of cervical carcinoma in situ, which can be effectively treated. The Pap test is probably the most effective cancer screening test developed to date. Most recently, vaccines protecting against two or four common oncogenic HPV subtypes have been approved for clinical use; if widely given to young women prior to initial HPV infection, these vaccines can prevent many cases of cervical cancer.⁴⁵

EBV and HHV8 are members of the herpesviridae family.⁴³ EBV, the cause of infectious mononucleosis, infects B lymphocytes and stimulates their proliferation. In individuals who are immunosuppressed because of HIV infection or because of drugs given for an organ transplant, persistent EBV infection can lead to the development of B-cell lymphomas. This development in those with organ transplants is known as post-transplant lymphoproliferative disorder (PTLD).⁴⁶ One effective therapy for PTLD is, if possible, to decrease or stop immunosuppressant drugs and allow the immune system to attack the virus. EBV infection also is associated with Burkitt lymphoma in areas of endemic malaria and with nasopharyngeal carcinoma, a cancer endemic in Chinese populations in Southeast Asia.⁴⁷ HHV8 is linked to the development of Kaposi sarcoma, a cancer that occurs in older adult men and in a markedly more virulent form in immunocompromised individuals, especially those infected with HIV. HHV8 also has been linked to several rare lymphomas.

Human T-cell leukemia-lymphoma virus (HTLV) is an oncogenic retrovirus linked to the development of adult T-cell leukemia and lymphoma (ATLL).⁴⁴ HTLV is transmitted vertically, that is, inherited by children from infected parents, and horizontally, by breast-feeding, sexual intercourse, blood transfusions, and exposure to infected needles. Infection with HTLV may be asymptomatic, and only a small fraction of infected individuals develop ATLL, often many years after acquiring the virus. It is clear that infection by an oncogenic virus is far from sufficient to cause cancer. For example, in some industrialized regions, Epstein-Barr virus can infect 90% of the adolescent and young adult population, yet only a very small percentage of these individuals develop EBV-related cancer. For each of these infections, important cofactors increase the risk that an infection will develop into cancer.

Bacterial Cause of Cancer

Helicobacter pyloriis a bacterium that infects more than half of the world’s population. Chronic infection with H. pylori is an important cause of peptic ulcer disease and is strongly associated with gastric carcinoma, a leading cause of cancer deaths worldwide. It is also associated with a less common cancer, gastric mucosa–associated lymphoid tissue (MALT) lymphomas.⁴⁸ H. pylori infection is often acquired in childhood and disproportionately affects lower socioeconomic classes. Although most infections are asymptomatic, prolonged chronic inflammation can lead to atrophic gastritis that can, in a small fraction of individuals, progress to dysplastic changes and finally frank gastric adenocarcinoma. Recent data have shown that H. pylori infection induces methylation of specific genes in the gastric mucosa.⁴⁹ Eradication of H. pylori from infected individuals prior to the development of dysplasia may prevent the development of cancer.⁵⁰ However, there is no expert consensus on the value of population screening and treatment strategies.⁵¹ The MALT lymphomas associated with chronic H. pylori infections may depend on chronic inflammation and antigenic stimulation associated with infections, and therefore treatment with antibiotics may be useful even in cases of early lymphoma.⁵²

Only Rare Cells in a Cancer Are Able to Metastasize

Metastasis is a highly inefficient process. A landmark clinical review examined a group of women with advanced ovarian cancer.⁵⁷ These unfortunate women had accumulated a large amount of peritoneal fluid filled with malignant ovarian cancer cells (malignant ascites). To relieve the pressure caused by the ascites, the fluid was surgically shunted into the venous circulation. This palliative procedure relieved the abdominal pressure but had the side effect of moving millions of ovarian cancer cells an hour directly into the bloodstream. Despite this direct injection of billions of cancer cells into the circulation, these women unexpectedly had no increased number of metastases when they died. The conclusion from this clinical study, that most cancer cells cannot successfully cause metastases, has been supported by many other clinical and laboratory studies as well.⁵⁶ The reason lies both in the seed and the soil. Cancer cells (the seeds) must surmount multiple physical and physiologic barriers in order to spread, survive, and proliferate in distant locations, and the destination (the soil) must be receptive to the growth of the cancer. It has been suggested that the metastatic cell must, like a decathlon champion, be successful in every event to allow a cancer to spread.⁵⁶

How do cancer cells develop the ability to metastasize? As cancers grow, they develop increasing heterogeneity. This reflects the genetic instability of cancer and aberrant differentiation of subclones of the malignant cells. The same changes that happen in cells to cause the primary cancer, including gene mutations, deletions, translocations, and epigenetic silencing, all work to provide genetic heterogeneity in the tumor cells as they proliferate. As this diversity increases, this increases the number of cells in the cancer mass with new abilities that can facilitate metastasis.

Detachment and Invasion

In order for cells to move away from their normal niche, they must be able to detach from the stroma and migrate. Cells are normally attached to extracellular matrix (ECM). Epithelial cells are further organized by basement membranes, a meshwork of collagens and other connective proteins. To facilitate cancer spread, many tumors and their associated inflammatory cells secrete proteases and protease activators, such as the matrix metalloproteinases (MMPs) and plasminogen activators. Active proteases digest the extracellular matrix and basement membranes, creating pathways through which cells can move, while releasing bioactive peptides as digestion products that further stimulate tumor growth and mobility. Recognition of the role of proteases led to the development of MMP inhibitors as a weapon against cancer progression. However, it is now recognized that there are also many proteases that block cancer proliferation, perhaps explaining why the first generation of MMP inhibitors showed little or no effect in clinical trials in treating cancer.⁵⁸

Another key mediator of cell detachment is the down-regulation in the cancer cell of specific adhesion molecules, such as E-cadherin and integrins. E-cadherin is commonly lost in cancers through diverse mechanisms including mutation, epigenetic silencing, proteolysis, and through a tissue remodeling process known as epithelial-mesenchymal transition (EMT) (regulated by the transcription factors with the evocative names Snail, Twist, and Slug). When E-cadherin is lost, cells are able to detach from their extracellular attachments and migrate away more readily.

Survival and Spread in the Circulation

Normal cells, when separated from their ECM, undergo anoikis, a form of apoptosis. In contrast, tumor cells that have already adapted to a hypoxic environment have already been selected for resistance to apoptosis, often by loss of normal cell death pathways. For example, neuroblastomas with loss of the proapoptotic caspase 8 genes are able to avoid apoptosis after loss of integrins, and are more able to metastasize than the same cells with normal levels of caspase 8. Accordingly, individuals whose neuroblastomas have low levels of caspase 8 have a poor prognosis.⁵⁹ (See Chapter 2.)

Selective Adherence in Favorable Sites

After release from the ECM and digestion of basement membranes, cancer cells gain access to the circulation through new tumor-associated blood vessel growth or angiogenesis (described earlier), also known as neovascularization. Mobile tumor cells are able to enter the circulation, perhaps facilitated by the leaky newly made vessels and attraction of the cells because of chemoattractants coming from these new vessels. Once in the circulation, metastatic cells must be able to withstand the physiologic stresses of travel in the blood and lymphatic circulation, including high shear rates and exposure to immune cells. One mechanism is for tumor cells to bind to blood platelets, giving them a protective coat of nonmalignant blood cells that both shields the tumor cells and creates a small tumor embolus, or cancer clot, that can promote cancer cell survival in distant locations.

The patterns of metastasis are dictated by the interaction between the cancer cells and the microenvironments in which they land. Two distinct mechanisms give rise to patterns of distant spread. First, cancer cells spread through vascular and lymphatic pathways, as well as natural tissue planes. The neovascularization of a cancer offers malignant cells direct access into the venous blood, and draining lymphatics can carry malignant cells to regional lymph nodes. Single cells, clumps, and even tumor fragments can disseminate by these routes. Anatomic patterns of lymphatic and venous blood flow help determine how colon cancers spread to the liver, liver cancers spread through the portal vein to the lungs, lung cancers spread through the systemic circulation to the brain, and breast cancer spreads through lymphatics to axillary lymph nodes (Figure 11-23). There is also a major yet poorly understood selectivity of different cancers for different sites. Thus metastatic breast cancer often spreads through the bloodstream to bones but rarely to kidney or spleen, whereas lymphomas often spread to the spleen but uncommonly spread to bone. In a key study, Schackert and Fidler⁶⁰ injected different types of cancer cells into the carotid artery of mice. Despite identical blood flow–mediated distribution of the cancer cells, each cancer cell type produced cancers in very different parts of the brain. This tissue selectivity is likely caused by specific interactions between the cancer cells and specific receptors on the small blood vessels in different organs (Table 11-8). Experimental metastasis studies in mice are beginning to reveal additional molecular reasons for this tissue specificity (Figure 11-24). Examples include interaction between α3β1 integrins binding to laminin-5 receptors in the lung, and the chemokine receptor CXCR4 on breast cancer cells promoting homing to lung tissues expressing the ligand CXCL12.⁵⁵

Escape from the Circulation and Development of a New Microenvironment

As the study with women with ovarian cancer illustrates, pumping millions of cancer cells in the bloodstream does not necessarily cause metastatic disease. Cancer cells may arrive in a new location and survive but not proliferate to form a clinically relevant metastasis. The tumor cells that do not make the transition from simple survival to robust proliferation in a new location are said to be in a state of dormancy. This dormancy may account for the observation that solitary tumor cells can be detected in the blood years after a complete clinical remission in individuals, and that many people with detectable micrometastases will not develop clinically obvious metastases.^61,62 One of the factors that allow proliferation of cancer cells in the new environment may be cancer’s recruitment of normal cells from local and circulating bone marrow stem cells. One developing concept is that successful metastatic tumor cells secrete factors that recruit circulating mesenchymal stem cells to the metastatic site (see Figure 11-12). These newly recruited stem cells then differentiate into tumor-supporting stroma and new blood vessels. One area of research is aimed at understanding why some micrometastases remain dormant; new therapies might block their progression to clinically important disease.

Clinical Manifestations of Cancer

Cancer Treatment

The diagnosis of cancer has a profound effect on individuals and their families. Responses range from depression to resigned fatalism to aggressive no-holds-barred pursuit of therapy. The decision as to what type of therapy to follow should be based on a full consideration by the individual, the family, and the medical team of the individual’s diagnosis, prognosis, and therapeutic options. Many types of cancer can be effectively treated with chemotherapy, radiotherapy, surgery, and combinations of these modalities. Caregivers must recognize that many individuals seek additional nonscience-based explanations and therapies and often use alternative therapies, either concurrently or sequentially. Alternative therapies can be biologically harmless or harmful; rarely is there any evidence they are medically effective and in the worst cases they can be expensive, delay the use of effective therapies, and produce unknown side effects. A challenge for the medical team is to provide the same level of psychosocial comfort and support that alternative therapies can provide, while also providing scientifically rational evidence-based therapies.

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