Terminology and the Formation of Cancer

Cells that give rise to progeny with the ability to expand in an uncontrolled manner will produce a tumor or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue is said to be benign. A tumor that continues to grow and becomes progressively more invasive is called malignant. The term cancer refers specifically to a malignant tumor. In addition to uncontrolled growth, most malignant tumors eventually exhibit metastasis or spread, whereby small clusters of cancerous cells dislodge from the original tumor, invade the blood or lymphatic vessels, and are carried to distant sites where they take up residence and continue to proliferate. In this way, a primary tumor at one site can give rise to a secondary tumor at another site (Overview Figure 19-1).

OVERVIEW FIGURE 19-1

Tumor Growth and Metastasis

(a) A single cell develops altered growth properties at a tissue site, which may be corrected via DNA repair. (b) The altered cell proliferates, forming a mass of localized tumor cells, or a benign tumor. (c) The tumor cells become progressively more invasive, spreading to the underlying basal lamina. The tumor is now classified as malignant. (d) The malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body.

The first illustration shows a sectional view of tissue with basal lamina, normal cells, and blood vessels labeled. The first stage in the forward direction is initiation. The second illustration shows the initially modified tumor cell in a different color. In the reverse direction, DNA repair happens, and the tumor cell becomes normal cell. The third illustration shows sectional view of tissue with the normal cells around the initial modified tumor cells also converted to tumor cells. This stage is called promotion. The fourth illustration shows few tumor cells traveling through the basal lamina to the inner tissue region. The cells that are moving inward are labeled Invasive tumor cells. This stage is called Progression. The fifth illustration shows tumor cells moving into the blood vessel. A callout pointing to the spreading cancerous cells reads, Metastatic tumor cells invade vessels and spread. This stage is called Metastasis.

Cancers are classified according to the embryonic origin of the tissue from which they arise. Most (80% to 90%) are carcinomas, tumors that develop from epithelial origins such as skin, gut, or the epithelial lining of internal organs and glands. Skin cancers and the majority of cancers of the colon, breast, prostate, and lung are carcinomas. Sarcomas arise less frequently and are derived from mesodermal connective tissues, such as bone, fat, and cartilage. These represent a small minority of cancers (about 1%) and are grouped into soft tissue sarcomas and osteosarcomas, or bone cancers. Last, there are cancers derived from blood cells, which make up approximately 9% of all malignancies. These can arise at multiple differentiated or undifferentiated stages of development.

Lymphomas, myelomas, and leukemias are all considered blood cell cancers, or malignancies arising in one of the many cell types derived from hematopoietic stem cells. What distinguishes them is the stage of differentiation, or where along the pathway from HSC to mature blood cell they arise. This can get complicated because, as we know from earlier chapters, leukocytes spend time in the bone marrow, secondary lymphoid tissues, the blood circulation, and even as mature residents in tissues. For this reason there is some overlap in the cell types and symptoms for these three types of blood cell cancer. In short, leukemias arise from cells that are still in their early stages of development in the bone marrow. These are classified as either myelogenous or lymphocytic, depending on which branch of the common progenitor they derive from. They are also classified as acute or chronic according to the clinical progression of the disease. Acute leukemia appears suddenly and progresses rapidly, whereas chronic leukemia is much less aggressive and develops slowly as a mild, barely symptomatic disease. These clinical distinctions apply to untreated leukemias; with current treatments, the acute leukemias often have a good prognosis, and permanent remission is possible.

Lymphomas and myelomas arise at later stages of blood cell development, typically after progenitors have migrated out of the bone marrow (although some of these cancerous cells will return to the bone marrow later). Lymphomas tend to spread through the lymphatic system and proliferate in secondary lymphoid organs; a common early symptom is one or more swollen lymph nodes. Myelomas arise from uncontrolled proliferation of fully differentiated B cells (plasma cells), producing a mutated form of antibody that can be found in the blood, called M protein. These cancers migrate to the bone marrow where they take up residence, often leading to bone pain and anemia. The term multiple myeloma comes from the fact that most affected individuals will present with multiple bone lesions, or more than one location where these cancerous plasma cells have taken up residence in bones.

Much has been learned about cancer from in vitro studies of primary cells, which are cells that have been isolated directly from the host and have a limited life span. Treatment of normal cultured cells with specific chemical or physical agents, irradiation, and certain viruses can alter their morphology and growth properties. In some cases, this process leads to unregulated growth and produces cells capable of growing as tumors when they are injected into animals. Such cells are said to have undergone transformation, or malignant transformation, and the agents that lead to cellular transformation are commonly referred to as carcinogens. Transformed cells often exhibit properties in vitro similar to those of cancer cells that form in vivo. For example, they have decreased requirements for the survival factors needed by most cells (such as growth factors and serum), are no longer anchorage or cell-contact dependent, and grow in a density-independent fashion with the ability to avoid apoptotic signals. Moreover, both cancer cells and transformed cells can be subcultured in vitro indefinitely; that is, for all practical purposes, they are immortal. Because of the similar properties of cancer cells and in vitro–transformed cells, the process of malignant transformation has been studied extensively as a model of cancer induction.

Accumulated DNA Alterations or Translocation Can Induce Cancer

Transformation can be induced by various chemical substances (such as formaldehyde, benzene, and some pesticides), physical agents (e.g., asbestos), and ionizing radiation; all are linked to DNA mutations. Infection with certain viruses, most of which share the property of integrating into the host cell genome and disrupting chromosomal DNA, can also lead to transformation. Table 19-1 lists the most common viruses associated with cancer. Although the activity of each of these agents is associated with cancer initiation, thanks to the variety of DNA repair mechanisms present in our cells, exposure to carcinogens does not always lead to cancer. Instead, a confluence of factors must occur before enough changes to normal cellular genes arise to induce malignant transformation, as we discuss further in the following sections.

TABLE 19-1 Common human infectious carcinogens

Viral agent	Type	Cancer
HTLV-1 (human T-cell leukemia virus-1)	RNA	Adult T-cell leukemia or lymphoma
HHV-8 (human herpesvirus-8)	DNA	Kaposi’s sarcoma (especially in HIV+ patients)
HPV (human papillomavirus)	DNA	Cervical carcinoma
HBV and HCV (hepatitis B and C viruses)	DNA	Liver carcinoma
EBV (Epstein-Barr virus)	DNA	Burkitt’s lymphoma and nasopharyngeal carcinoma

Data sources: The National Institute for Occupational Safety and Health (NIOSH) and the Centers for Disease Control and Prevention (CDC) (see http://www.cdc.gov/niosh/topics/cancer/).

Some transformations arise when chromosomal translocations alter the expression and regulation of certain genes. For instance, a number of B- and T-cell leukemias and lymphomas arise from translocations involving immunoglobulin or T-cell receptor loci, very transcriptionally active regions in these cells, to other areas of the DNA. One of the best characterized is the translocation of myc from its position on chromosome 8 to the immunoglobulin heavy-chain enhancer region on chromosome 14, accounting for 75% of Burkitt’s lymphoma cases (Figure 19-2). In the remaining patients with Burkitt’s lymphoma, myc remains on chromosome 8 but the κ or λ light-chain genes are translocated to the tip of chromosome 8, near the myc gene region and inducing a similar change. As a result of these translocations, synthesis of the Myc protein, which functions as a transcription factor controlling the behavior of many genes involved in cell growth and proliferation, increases and allows unregulated cellular growth.

FIGURE 19-2 Chromosomal translocations resulting in Burkitt’s lymphoma. (a) Most cases of Burkitt’s lymphoma arise following a chromosomal translocation that moves part of chromosome 8, containing the c-myc gene, to the Ig heavy-chain locus on chromosome 14, shown in more detail in (b). (c) In some cases, the entire c-myc gene is inserted near the Ig heavy-chain enhancer. (d) In other cases, only the coding exons (2 and 3) of c-myc are inserted at the μ switch site. The proto-oncogene myc encodes a transcription factor involved in the regulation of many genes with roles in cell growth, proliferation, and inhibition of apoptosis.

Section a shows gene translocation between chromosome 8 and 14. Chromosome 8 has c–myc c–myc gene and chromosome 14 has C H and V H genes. The c–myc of chromosome 8 moves to chromosome 14 while V H of chromosome 14 moves to chromosome 8. The translocated chromosome 8 is now called 8 q minus and the translocated chromosome 14 is called 14 q plus.

Section b shows the sequence of the rearranged I g heavy-chain gene on chromosome 14. The sequence reads as follows from the 5 dash end to the 3 dash end: Promoter - L - V H - D - J H - J H - J H - Enhancer - S mu (Switch region) - C mu exon (repeated 6 times).

Section c shows the sequence of the Translocated c–myc gene in some Burkitt’s lymphomas. The gene sequence reads as follows from the 5 dash end to the 3 dash end: 3 c-myc exon - 2 c-myc exon - 1 c-myc exon - Line break - Enhancer - S mu - C mu exons (repeated 6 times).

Section d shows Translocated c–myc gene in other Burkitt’s lymphomas. The gene sequence reads as follows from the 5 dash end to the 3 dash end: 3 c-myc exon - 2 c-myc exon - S mu - C mu exons (repeated 6 times).Section a shows gene translocation between chromosome 8 and 14. Chromosome 8 has c–myc c–myc gene and chromosome 14 has C H and V H genes. The c–myc of chromosome 8 moves to chromosome 14 while V H of chromosome 14 moves to chromosome 8. The translocated chromosome 8 is now called 8 q minus and the translocated chromosome 14 is called 14 q plus.

Section b shows the sequence of the rearranged I g heavy-chain gene on chromosome 14. The sequence reads as follows from the 5 dash end to the 3 dash end: Promoter - L - V H - D - J H - J H - J H - Enhancer - S mu (Switch region) - C mu exon (repeated 6 times).

Section c shows the sequence of the Translocated c–myc gene in some Burkitt’s lymphomas. The gene sequence reads as follows from the 5 dash end to the 3 dash end: 3 c-myc exon - 2 c-myc exon - 1 c-myc exon - Line break - Enhancer - S mu - C mu exons (repeated 6 times).

Section d shows Translocated c–myc gene in other Burkitt’s lymphomas. The gene sequence reads as follows from the 5 dash end to the 3 dash end: 3 c-myc exon - 2 c-myc exon - S mu - C mu exons (repeated 6 times).

Key Concept:

• Cancer-causing agents (carcinogens) and random events that damage DNA, including some viral infections and chromosomal translocations, can accumulate into a condition that allows unregulated cell proliferation and cellular transformation.

Genes Associated with Cancer Control Cell Proliferation and Survival

Normal tissues maintain homeostasis through a tightly controlled process of cell proliferation balanced by regulated cell death, or apoptosis. An imbalance at either end of the scale can encourage development of a tumor. The genes involved in these homeostatic processes work by producing proteins that either encourage or discourage cellular proliferation and survival. Not surprisingly, it is the disruption of these same growth-regulating genes that accounts for most, if not all, forms of cancer. The activities of these proteins can occur anywhere in the cell cycle pathway, from signaling events at the surface of the cell, to intracellular signal transduction processes and nuclear events.

Normal cellular genes that are associated with the formation of cancer fall into three major categories based on their activities (Table 19-2):

• Oncogenes—sequences that encourage growth and proliferation
• Tumor-suppressor genes—sequences that discourage or inhibit cell proliferation
• Apoptosis genes—sequences that control programmed cell death

TABLE 19-2 Functional classification of cancer-associated genes

Type/name	Nature of gene product
CATEGORY I: PROTO-ONCOGENES THAT INDUCE CELLULAR PROLIFERATION
Growth factors sis	A form of platelet-derived growth factor (PDGF)
Growth factor receptors fms erbB neu erbA	Receptor for colony-stimulating factor 1 (CSF-1) Receptor for epidermal growth factor (EGF) Protein (HER2) related to EGF receptor Receptor for thyroid hormone
Signal transducers src abl Ha-ras N-ras K-ras	Tyrosine kinase Tyrosine kinase GTP-binding protein with GTPase activity GTP-binding protein with GTPase activity GTP-binding protein with GTPase activity
Transcription factors jun fos myc	Component of transcription factor AP1 Component of transcription factor AP1 DNA-binding protein
CATEGORY II: TUMOR SUPRESSOR GENES, INHIBITORS OF CELLULAR PROLIFERATION*
Rb	Suppressor of retinoblastoma
TP53	Nuclear phosphoprotein that inhibits formation of small-cell lung cancer and colon cancers
DCC	Suppressor of colon carcinoma
APC	Suppressor of adenomatous polyposis
NF1	Suppressor of neurofibromatosis
WT1	Suppressor of Wilms’ tumor
CATEGORY III: GENES THAT REGULATE PROGRAMMED CELL DEATH OR APOPTOSIS
bcl-2	Suppressor of apoptosis
Bcl-xL	Suppressor of apoptosis
Bax	Inducer of apoptosis
Bim	Inducer of apoptosis
Puma	Inducer of apoptosis

^*The activity of the normal products of the category II genes inhibits progression of the cell cycle. In most cases, loss or inactivation of both copies of a tumor suppressor gene is required for development of cancer.

Oncogenes are involved in cell growth–promoting processes, while tumor-suppressor genes play the opposite role in homeostasis: dampening cellular growth and proliferation. Unlike oncogenes, which become the villain when their activity is enhanced, tumor-suppressor genes, also known as anti-oncogenes, become involved in cancer induction when they fail. Finally, many of the genes involved in apoptosis are also associated with cancer, as these genes either enforce or inhibit the cell death signals.

Oncogenes

A proto-oncogene is a normal cellular gene involved in some aspect of cell growth and proliferation. When proto-oncogenes are mutated or subject to dysregulation, the change in expression can lead to uncontrolled cell proliferation, or cancer. The mutated form of a proto-oncogene that can induce cancer is called an oncogene, from the Greek word ónkos (which means “mass” or “tumor”).

One category of proto-oncogenes encodes growth factors and growth factor receptors. In normal cells, the expression of growth factors and their receptors is carefully regulated. Inappropriate expression of either a growth factor or its receptor can result in uncontrolled proliferation. For instance, in some breast cancers, increased synthesis of the growth factor receptor encoded by c-neu has been linked with cancer development and disease progression. Included within this category are the genes fms, erbA, and erbB, all of which encode growth factor receptors (see Table 19-2). Mutations in cancer-associated genes may be a major mechanism by which chemical carcinogens or x-irradiation convert a proto-oncogene into a cancer-inducing oncogene. For instance, single-point mutations in c-ras, which encodes a GTPase, have been detected in carcinomas of the bladder, colon, and lung. Alterations that result in overactivity of the ras oncogene, part of the epidermal growth factor (EGF) receptor signaling pathway, are seen in up to 30% of all human cancers and nearly 90% of all pancreatic cancers.

Likewise, signal transduction processes are another potential target for disruptions that can lead to cancer. The src and abl oncogenes encode tyrosine kinases. The products of these genes act as signal transducers, upstream of transcription factors acting on their DNA targets. Not surprisingly, myc, jun, and fos are all oncogenes that encode transcription factors involved in cell proliferation and cell cycle progression. Overactivity of any of the genes in these common pathways, from ligand binding to signal transduction and transcription factor translocation to the nucleus, can thus result in unregulated cell proliferation.

Finally, some infectious agents can themselves act as initiators of uncontrolled cell proliferation. In particular, viral integration into the host-cell genome may serve to transform a proto-oncogene into an oncogene. For example, avian leukosis virus (ALV) is a retrovirus (RNA virus) that does not carry any viral oncogenes, yet it is able to transform B cells into lymphomas. This particular retrovirus has been shown to integrate within the c-myc proto-oncogene, resulting in increased synthesis of the Myc protein. Some DNA viruses have also been associated with malignant transformation, such as certain serotypes of the human papillomavirus (HPV), which are linked with cervical cancer (see Table 19-1).

Tumor-Suppressor Genes

Tumor-suppressor genes, or anti-oncogenes, encode proteins that inhibit cell proliferation. In their normal state, tumor-suppressor genes prevent cells from progressing through the cell cycle inappropriately, functioning like brakes on a car. A release of this inhibition is what can lead to cancer induction. The prototype of this category of oncogenes is Rb, the retinoblastoma gene (see Table 19-2). Hereditary retinoblastoma is a rare childhood cancer in which tumors develop from neural precursor cells in the immature retina. The affected child inherits a mutated Rb allele; later, somatic inactivation of the remaining Rb allele is what leads to tumor growth. Unlike oncogenes where a single allele alteration can lead to unregulated growth, tumor-suppressor genes require a “two-hit” disabling sequence, as one functional allele is typically sufficient to suppress the development of cancer.

Probably the single most frequent genetic abnormality in human cancer, found in 60% of all tumors, is a mutation in the TP53 gene. This tumor-suppressor gene encodes p53, a nuclear phosphoprotein with multiple cellular roles, including growth arrest, DNA repair, and apoptosis. Over 90% of small-cell lung cancers and over 50% of breast and colon cancers have been shown to express mutations in TP53.

Apoptosis Genes

A third category of cancer-associated genes is sequences involved in programmed cell death, or apoptosis. Genes associated with apoptosis can act as either inhibitors or promoters of this pathway. Pro-apoptotic genes act like tumor suppressors, normally inhibiting cell survival, whereas anti-apoptotic genes behave more like oncogenes, promoting cell survival. Thus, a failure of the former or overactivity of the latter can encourage neoplastic transformation of cells.

Included in this category are genes such as bcl-2, an anti-apoptosis gene (see Table 19-2). This oncogene was originally discovered because of its association with B-cell follicular lymphoma. Since its discovery, bcl-2 has been shown to play an important role in regulating cell survival during hematopoiesis and in the survival of selected B cells and T cells during maturation. Interestingly, the Epstein-Barr virus, which can cause infectious mononucleosis, contains a gene that has sequence homology to bcl-2 and may act in a similar manner to suppress apoptosis. Like tumor suppressors, in many cases the products of these genes function as “checkpoints” in the cell cycle.

Key Concepts:

• Oncogenes are typically DNA sequences that encode proteins involved in promoting cell growth and proliferation, such as transcription factors, growth factors (and their receptors), or intracellular signaling molecules.
• Tumor suppressors act naturally as anti-oncogenes or inhibitors of cell growth and proliferation, becoming agents of transformation when they fail to function, such as during DNA repair or in blocking progression through cell cycle checkpoints.
• When the DNA sequences involved in apoptosis, or programmed cell death, are not functioning properly they also can aid in cellular transformation, encouraging the survival and proliferation of neoplastic cells.

Malignant Transformation Involves Multiple Steps

Promotion of a cancerous state doesn’t just happen overnight. Instead, it arises from a series of small changes, each taking the cell one step closer to uncontrolled replication. This multistep process of clonal evolution is driven by a series of somatic mutations. In fact, the early genetic changes that begin this cascade are sometimes called “driver” mutations, which are later followed by “passenger” mutations that come along for the ride but also foster the development of cancer. Clinical investigations in humans have suggested that as few as two and as many as eight key genes may serve as the original drivers for the development of cancer, with a long list of possible passenger mutations that, while less critical to initiation, also contribute to malignancy. Collectively, these genetic changes progressively convert the cell from normal growth to a malignant state where each of the regular checkpoints that control proliferation has been surmounted.

Sequential Genetic Disruptions

Induction of malignant transformation appears to evolve in distinct phases, referred to as initiation, promotion, progression, and metastasis. Initiation involves changes or mutations in the genome that alter cell proliferation potential but do not, in themselves, lead to malignant transformation. The next stage, promotion, occurs when preneoplastic cells gradually begin to accumulate. At this stage tumor size is generally small and the cells are still amenable to repair mechanisms. Importantly, these first two stages in the transformation process can last for long periods and the cells are still susceptible to immune-mediated detection and chemopreventive agents, with the potential to reverse the course of disease.

Progression tends to move more quickly than the previous two phases. Genetic alterations occurring here allow for rampant cell proliferation and the acquisition of new mutations to potential cancer-promoting genes, exacerbating the cycle. As expected, tumor sizes can grow rapidly in this stage. When one or more of these rapidly dividing cells acquire mutations that allow invasion of nearby tissue, the situation has progressed to the final stage, metastasis. By definition, metastatic cancers that come from solid tissues have lost adhesion with neighboring cells and no longer exhibit contact inhibition. This allows them to move outside the original site and even enter blood or lymphatic vessels, where they can then spread through the body. One example that clearly illustrates the type of natural progression that can lead to cellular transformation comes from human colon cancer, which typically develops in a series of well-defined morphologic stages (Figure 19-3). Colon cancer begins as small, benign tumors called adenomas in the colorectal epithelium. These precancerous tumors grow, gradually displaying increasing levels of intracellular disorganization until they acquire the malignant phenotype, or carcinoma (see Figure 19-3b). The morphologic stages of colon cancer have been correlated with a sequence of gene changes (see Figure 19-3a) involving inactivation or loss of three tumor-suppressor genes (APC, DCC, and TP53) and activation of one cellular proliferation oncogene (K-ras).

FIGURE 19-3 Model of sequential genetic alterations leading to metastatic colon cancer. Each of the stages indicated in (a) is morphologically distinct, as illustrated in (b), allowing researchers to determine the sequence of genetic alterations. In this sequence, benign colorectal polyps can progress to carcinoma following mutations resulting in the inactivation or loss of three tumor-suppressor genes (APC, DCC, and TP53) and the activation of one oncogene linked to cellular proliferation (K-ras).

Section a shows a flow diagram explaining the genetic and morphological changes that lead to metastatic colon cancer. In chromosomal site 5 q, loss of gene A P C occurs, leading to conversion of Normal Epithelium to Hyperproliferative epithelium. DNA hypomethylation occurs, leading to formation of early adenoma from the Hyperproliferative epithelium. In chromosomal site 12 p, activation of K-ras gene occurs. This triggers the formation of intermediate adenoma from early adenoma. In chromosomal site 18 q, loss of gene D C C happens, leading to formation of late adenoma from intermediate adenoma. Loss of gene T P 53 in chromosomal site 17 p leads to formation of carcinoma from late adenoma. Due to other alterations, carcinoma becomes metastasis. Section b shows a flow diagram explaining the process of conversion of normal cells to carcinoma cells as above. Each step is accompanied by an illustration. The first illustration shows a layer of colon cells with one cell in a different color. In the second illustration, the cells adjoining the different colored cell, also changing color. The third illustration shows only the differently colored cells proliferating. The fourth illustration shows the colored cells spreading to other areas and also proliferating to form a lump-like structure. The fifth illustration shows colored cells forming a larger lump. A few colored cells are in a different shape and are shown moving away from the lump-like structure.

Studies with transgenic mice also support the role of multiple steps in the induction of cancer. Transgenic mice expressing high levels of Bcl-2, a protein encoded by the anti-apoptotic gene bcl-2, develop a population of small resting B cells (derived from secondary lymphoid follicles) that have greatly extended life spans. Gradually, these transgenic mice develop lymphomas. Analysis of lymphomas from these animals has shown that approximately half have a c-myc translocation (a proto-oncogene) to the immunoglobulin H-chain locus. The synergism of Myc and Bcl-2 is highlighted in double-transgenic mice produced by mating the bcl-2 ⁺ transgenic mice with myc⁺ transgenic mice. These mice develop leukemia very rapidly.

Hallmarks of Cancer

Examples of the genetic mutations typical of cellular transformation have helped scientists to establish some interesting common denominators for cancer. By definition, all neoplastic cells display a selective growth advantage over their peers. However, imbedded within this simple statement lie several unifying themes. Data from genomic studies in humans and animals have coalesced into a picture of cancer as a series of DNA alterations that amount to “order within chaos,” all leading to the same ultimate endpoint. In 2000, Hanahan and Weinberg suggested a set of six defining characteristics that distinguish the cancer cell, and a decade later, in 2011, they modified this list to include four more overarching and linked conditions (Figure 19-4). The original cancer-causing DNA alterations cluster around three essential cellular processes: cell fate determination, genome maintenance, and cell survival. The four conditions later added to this picture of cancer include genome instability, altered metabolic pathways, chronic inflammation, and immune avoidance patterns. As discussed below, these observations are linked to a burst of immune-based therapies aimed at the treatment of cancer.

FIGURE 19-4 Hallmarks of cancer. Shown in the center are the six original hallmarks proposed as common characteristics of cancer. Later, two enabling characteristics were added as an overlay or microenvironmental factor: genome instability and protumor inflammation. Finally, two newly emerging hallmarks were added to the observed cancer profile: changes in cellular energetics and immune evasion.

An illustration of tissue sectional view is placed above six broad arrows leading from Enabling characteristics to Emerging hallmarks. The enabling characteristics are Genome instability and tumor-promoting inflammation while the emerging hallmarks are Changing cellular energetics and evasion of immune destruction. The tissue sectional view shows Immune inflammatory cells (I Cs), Invasive cancer cell, Cancer stem cell (CSC), and Cancer cell (C C). Six callouts pointing to the tissue section reads, Sustaining proliferative signaling, Evading growth suppressors, Activating invasion and metastasis, Enabling replicative immortality, Inducing angiogenesis, and Resisting call death.

In the face of these unifying themes related to cancer, evidence has emerged also for heterogeneity within the cancer cell population. Clinical studies of at least three different types of tumors, including those originating in the gut, brain, and skin, suggest that a subset of cells within a tumor may be the real engines of tumor growth. This subset, called cancer stem cells, displays true unlimited regenerative potential and is the major producer of new cells to feed the tumor. Nonstem cells each undergo unique mutations and differentiate in novel ways. This gives cancer an advantage in terms of renewal potential and immune evasion. Nonstem cells constitute the bulk of the growing edges of the tumor and thus serve as the primary immune targets—like decoys. These rapidly mutating cells express an ever-evolving set of new protein markers, with the potential to serve as targets for the immune response. However, there is little risk if these proteins are recognized and lead to immune destruction; their undifferentiated stem cell parent remains as a source of replacement.

Key Concepts:

• Cellular transformation occurs as the result of multiple gene mutations that accumulate in several genes over time, and gradually subvert the normal checks on cell growth and survival.
• Malignant cells display alterations in key cellular processes and microenvironmental conditions: cell fate decisions, genome maintenance, cell survival, genetic instability, metabolic changes, and immune response patterns.