Chapter 7: Neoplasia Flashcards
Definition of neoplasia
“New growth”
a.k.a. neoplasm
Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues and persists in the same excesive manner after cessation of the stimuli which evoked the change.
Composed of parenchyma (neoplastic cells) and stroma (fibrovascular support tissue with immune cells)
Desmoplasia definition
A tumor’s production of abundant collagenous stroma - may cause scirrhous (stony hard) tissue
Benign tumors
A tumor is said to be benign when its gross and microscopic appearances are considered relatively innocent, implying that it will remain localized, will not spread to other sites, and is amenbable to local surgical removal.
While the patient usually survives, benign tumors can cause significant morbidity, and may be fatal.
Neoplasia nomenclature
Benign tumors
Benign tumor suffix -oma (e.g. fibroma, chondroma)
mesenchymal tumors follow this rule, epithelial benign tumors are more complex
Benign epithelial tumor from galnds -adenoma (renal, adrenal, hepatic, etc.). These may or may not form glandular structures.
Benign epithelial tumors with warty projections -papilloma
Benign eipthelial tumors forming large cystic masses -cystadenoma
Polyp - when a neoplasm (benign or malignant) makes a macroscopic projection above a mucosal surface (e.g. colon, stomach)
Malignant tumors
Cancer - Malignant tumor. These can invade and destroy adjacent structures, and spread to distant sites (metastasize) to cause death.
Malignant tumor of solid mesenchymal tissue -sarcoma (e.g. fibrosarcoma, chondrosarcoma)
Malignant tumor from blood-forming cells -leukemia, lymphomas
Malignant neoplasm of epithelial cell origin (from any of the three germ layers) - carcinomas
Malignant epithelial tumor from glands -adenocarcinoma (e.g. renal cell adenocarcinoma)
Mixed tumor - Neoplasm (benign or malignant) that contains epithelial and mesenchymal components, due to divergent differentiation of a single neoplastic clone (e.g. mixed tumor of the salivary gland, mixed canine mammary tumor) - these are far rarer than simple tumors
- Teratoma* (Exceedingly rare) - Contains recognizable mature or immature cells or tissues belonging to more than one germ cell layer (sometimes all three). Originates from totipotential germ cells which are normally present in ovary/testis and can differentiate into any cell type in the adult body (e.g. ovarian cystic teratoma a.k.a. dermoid cyst - may contain sebaceous glands or teeth…)
- Hamartoma-* disorganized, benign masses of cells indigenous to the involved site
- Choriostoma* - heterotopic rest o cells (e.g. normal pancreatic tissue in stomach, intestines) - no clinical significance
Colonic polyp.
A, An aedonmatous (glandular) polyp is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk.
B, Gross appearance of several colonic polyps.
This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resemble cartilage.
A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth.
B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.
Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles.
Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor (last card), the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered differentiated because gland formation is seen. The malignant glands have invaded the muscular layer of the colon.
Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow).
Anaplastic tumor showing cellular and nuclear variation in size and shape. The prominent cell in the center field has an abnormal tripolar spindle.
Pleomorphic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
A, Carcinoma in situ. A low-power view shows that the epithelium is entirely replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact, and there is no tumor in the subepithelial stroma.
B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface.
Differentiation and anaplasia
Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia.
In general, benign tumors are well differentiated.
While malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature.
(Exceptions include well-differentiated SCCs and thyroid carcinomas)
Lack of differentiation, or anaplasia, is considered a hallmark of malignancy.
Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.
Microscopic view of fibroadenoma of the breast seen in last card. The fibrous capsule (right) delimits the tumor from the surrounding tissue.
Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation.
Low power microscopic view of invasive breast cancer. Note the irregular infiltrative borders without a well-defined capsule and intense stromal reaction.
Colon carcinoma invading pericolonic adipose tissue.
Axillary lymph node with metastatic breast carcinoma. Note the aggregates of tumor cells within the substance of the node and the dilated lymphatic channel.
A liver studded with metastatic cancer.
Microscopic view of lung metastasis. A colonic adenocarcinoma has formed a metastatic nodule in the lung.
KEY CONCEPTS - Characteristics of benign and malignant neoplasms
TABLE - Comparison between benign and malignant tumors
Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of the same origin (leiomyosarcoma).
KEY CONCEPTS - Epidemiology of cancer
Morphologic changes associated with lack of differentiation/anaplasia
1. Pleomorphism - variation in size and shape
2. Abnormal nuclear morphology - Usually the nucleus is disproportionately large for the cell, causing high N:C ratio, shape is variable and often irregular, chromatin is coarsely clumped and distributed around the membrane or more darkly stained than normal (hyperchromatic)
3. Mitoses - Many cells are in mitosis in poorly differentiated neoplasms, (high proliferative activity). The presence of mitoses does not necessarily indicate malignancy. However, very frequent, or atypical/bizzare mitotic figures are a more important feature.
4. Loss of polarity - Orientation of cells is disturbed - sheets or large masses of tumor cells grow in an anarchic, disorganized fashion
5. Other changes - Many malignant and some benign tumors may develop large central areas of ischemic necrosis due to insufficient vascular stroma.
Development of a cancer through stepwise acquisition of complementary mutations. The order in which various driver mutations occur in initiated precursor cells is not known and may vary from tumor to tumor.
Metaplasia and dysplasia
- Metaplasia -* replacement of one type of cell with another type; nearly always found in association with tissue damage, repair, and regeneration (e.g. gastroesophageal reflux damages esophageal squamous epithelium –> replacement by glandular (gastric/intestinal) epithelium more resistant to acid)
- Dysplasia* - Disordered growth; usually in epithelial cells; loss in uniformity and architectural orientation (e.g. squamous cells losing the tall to flattened differentiation, and all appearing basilar)
When dysplastic changes are marked and involve the full thickness of the epithelium, but the lesion does not penetrate the basement membrane, it is considered a pre-neoplastic neoplasm, and is referred to as carcinoma in situ. Once tumors breach the BM, tumor is invasive. It does not always lead to cancer.
Often seen adjacent to invasive carcinoma, or in long-term cig smokers, it precedes cancer formation. It often occurs in metaplastic epithelium, but not all metaplastic epithelium is dysplastic.
Tumor evolution. Evolution of a renal cell carcinoma (left panel) and Darwin’s finches (right panel). The renal cell carcinoma evolutionary tree is based on genetic comparisons drawn from sequencing of DNA obtained from different tumor sites; the finch evolutionary tree was surmised by Darwin based on morphologic comparisons of different species of finches on the Galapagos Islands.
Hallmarks of cancer.
Local invasion
The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue, whereas nearly all benign tumors grow as cohesive, expansile masses that remain localized to their site of origin, and lack the capacity to infiltrate, invade, or metastasized to distant sites.
Benign tumors often contain a fibrous capsule, separating them from surrounding tissue, thus are easily excisable (exceptions - hemangiomas are unencapsulated).
Malignant tumors are poorly demarcated from surrounding tissue
Next to the development of metastases, invasiveness is the most reliable feature that differentiates cancers from benign tumors.
TABLE: Selected oncogenes, mode of activation, associated human tumors
Growth factor signaling pathways in cancer. Growth factor receptors, RAS, PI3K, MYC, and D cyclins are oncoproteins that are activated by mutations in various cancers. GAPs apply brakes to RAS activation, and PTEN serves the same function for PI3K.
Metastasis
Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor, and unequivocally marks a tumor as malignant, as by definition, benign tumors do not metastasize.
All malignant tumors can metastasize; due to innate invasiveness, they can penetrate into blood vessels, lymphatics, and body cavities, through which they can spread. Some cancers metastasize very infrequently (e.g. gliomas, basal cell carcinomas of skin).
Likelihood ofmetastasizing correlates with lack of differentiation, aggressive local invasion, rapid growth, and large size; WITH MANY EXCEPTIONS
Three pathways through which cancers can disseminate
1. Seeding of body cavities and surfaces - Occurs when neoplasm penetrates into open cavitary spaces (usually peritoneal, can be any); more common in epithelial neoplasms; coats body cavitary surfaces with heavy cancerous glaze; mucus-secreting appendiceal/ovarian carcinomas can fill cavity with a gelatinous neoplastic mass called pseudomyxoma peritonei
- *2. Lymphatic spread** - Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas; sarcomas may use this route too.
- *A sentinel lymph node is defined as the first node in a regional lymphatic basin that receives lymph flow from the primary tumor, and can be biopsied to assess presence or absence of metastatic lesion.**
3. Hematogenous spread - Typical of sarcomas, also seen with carcinomas. Veins have thinner walls and are more easily penetrated, but arterial involvement can happen at AV shunts or pulmonary capillary beds.
Liver and lungs are most frequent first sites of hematogenous spread because of portal and pulmonary circulation.
The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia.
What are some of the broad predisposing factors to neoplasia?
- Environmental factors
- Age
- Acquired predisposing conditions
- Genetic Predisposition
TABLE: Cell cycle components and inhibitors that are frequently mutated in cancer
KEY CONCEPTS: Oncogenes, oncoproteins, and unregulated cell proliferation
Environmental factors predisposing to neoplasia
Lthough both genetic and environmental factors contribute to the development of cancer, environmental influences appear to be the dominant risk factor for most cancers.
This is evidenced by the wide geographic variation in specific types of cancer.
Infectious agents: 15% of all cancers worldwide caused by infectious agents (HPV - cervical carcinoma, EBV - lymphoma)
Smoking: Cig smoking is the single most important environmental factor causing premature death in the US (larynx, mouth, pharynx, esophagus, pancreas, bladder, lung cancers)
Alcohol consumption
Diet:specifics unknown, but important factor
Obesity: 52-62% higher incidence of cancer than normies
Reproductive history: little is known
Environmental carcinogens: UV rays, smog, arsenic in water, medications (methotrexate), asbestos
Age predisposing to cancer
Age has an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur later in life (> 55 years)
Cancer is the main cause of death in women 40-79, and men 60-79. Lower incidence after 80, because cancer patients do not live that long.
Cancer accounts for > 10% of deaths in children under 15yo in US. They get different types (small round blue cell tumors (neuroblastoma, Wilms tumor, retinoblastoma, acute leukemias, rhabdomyosarcoma)
Acquired predisposing conditions to neoplasia
Acquired conditions that predispose to cancer can be divided into chronic inflammations, precursor lesions, and immunodeficiency states.
1. Chronic inflammation: usually carcinomas, but also mesothelioma and several types of lymphoma. Chronic inflammation leads to tissue repair and an increase in number of tissue stem cells., which are susceptible to neoplastic transformation. Immune cells involved in inflammation produce genotoxic ROS and inflammatory mediators that promote cell survival in the face of DNA damage. Chronic inflam leads to metaplasia, so cells are more able to survive ongoing insult.
2. Precursor lesions: localized morphologic changes associated with a high risk of cancer.
May arise in the setting of chronic inflammation and metaplasia (e.g. Barrett esophagus - gastric/colonic metaplasia in esophageal mucosa with gastric reflex; squamous metaplasia of bronchial mucosa with smoking).
Others are noninflammatory hyperplasias (e.g. endometrial hyperplasia with sustained estrogen stimulation; leukoplakia: thickening of squamous epithelium in oral cavity, penis, vulva, may lead to SCC)
Last group is benign neoplasms at risk for malignant transformation (colonic villous adenoma progresses to cancer in 50% of untreated cases)
3. Immunodeficiency states and cancer: Immunodeficient patients, especially with T-cell deficits have increased risk for oncogenic virus-inducing cancers (lymphomas, certain carcinomas, rare sarcomas)
4. Genetic predisposition: Some families have cancer as an inherited trait, usually due to mutations in tumor suppression gene. There is a complex interaction between genetic and nongenetic factors. Breast cancer has a strong hereditary component, but also is influenced by reproductive history.. Inherited variations (polymorphisms) of enzymes that metabolize procarcinogens to active carcinogenic forms can influence cancer susceptibility (cytochrome P-450 enzymes)
TABLE: Selected tumor suppressor genes and associated familial syndromes and cancers
Pathogenesis of retinoblastoma. Two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the sporadic form, both RB mutations in the tumor-founding retinal cell are acquired. In the familial form, all somatic cells inherit one mutated copy of RB gene from a carrier parent, and as a result only one additional RB mutation in a retinal cell is required for complete loss of RB function.
The role of RB in regulating the G1-S checkpoint of the cell cycle. Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin-remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by cyclin-dependent kinase inhibitors, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16). TGF-β, transforming growth factor-β.
KEY CONCEPTS: RB, Governor of the Cell Cycle
Genetic origins of cancerare very complex, and are only recently being elucidated. These 6 certain “genomic themes” have emergefd that are likely relevant to every cancer.
1. Nonlethal genetic damage lies at the heart of carcinogenesis. Initial damage may be environmental (viruses, chemicals, endogenous metabolites), inherited, or spontaneous and random
2. A tumor is formed by the clonal expansion of a single precursor cell that has incurred enetic damage (i.e. tumors are clonal). All cells of the tumor have the same set of mutations present at the moment of transformation. Identified by DNA sequencing (point mutations) or chromosomal analyses (chromosomal translocations and copy number changes)
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3. Four classes of normal regulatory genes - the growth promoting proto-oncogenes, the growth-inhibiting tumor suppressor genes, genes that regulate programmed cell death (apoptosis), and genes involved in DNA repair** - are the principal targets of cancer-causing mutations.
(1) Mutations in proto-oncogenes–> “gain-of-function” –> can transform cells when heterozygous
(2) Mutations in tumor suppressor genes –> “loss-of-function” –> both alleles must be damaged for transformation. Exception: haploinsufficiency- reduces activity of protein enough to release brakes on cell proliferation/survival
(3) Apoptosis-regulating gene mutations result in less death, enhanced survival; can be gain-of-function for genes whose products suppress apoptosis or loss-of-function for genes whose products promote apoptosis
(4) Mutations in DNA repair genes: Loss-of-function mutations impair cell ability to recognize and repair nonlethal genetic damage –> affected cells acquire mutations at an accelerated rate (mutator phenotype*, marked by genomic instability)
4. Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time. Malignant neoplasms have several phenotypic alterations known as cancer hallmarks (excessive growth, local invasiveness, distant mets)
5. Mutations that contribute to teh development of the malignant phenotype are referred to as driver mutations. The initiating mutation is teh first driver starting a cell on the path to malignancy, and is present in all cells of the cancer. “Initiated” cell acquires numerous further driver mutations, which all contribute to development of cancer.
6. Loss-of-function mutations in genesthat maintain genomic integrity appear to be a common early step on teh road to malignancy, particularly in solid tumors. These mutations lead to increased likelihood of acquiring driver mutations, and increased frequency of mutations that have no phenotypic consequence, passenger mutations.
The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair by transcriptional upregulation of the cyclin-dependent kinase inhibitor CDKN1A (encoding the cyclin-dependent kinase inhibitor p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of the p53 gene, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
KEY CONCEPTS: p53, Guardian of the Genome
Other tumor suppressor genes
The role of APC in regulating the stability and function of β-catenin. APC and β-catenin are components of the WNT signaling pathway.
A, In resting colonic epithelial cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low.
B, When normal colonic epithelial cells are stimulated by WNT molecules, the destruction complex is deactivated, β-catenin degradation does not occur, and cytoplasmic levels increase. β-catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates genes involved in cell cycle progression. C, When APC is mutated or absent, as frequently occurs in colonic polyps and cancers, the destruction of β-catenin cannot occur. β-catenin translocates to the nucleus and coactivates genes that promote entry into the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.
Metabolism and cell growth. Quiescent cells rely mainly on the Krebs cycle for ATP production; if starved, autophagy (self-eating) is induced to provide a source of fuel. When stimulated by growth factors, normal cells markedly upregulate glucose and glutamine uptake, which provide carbon sources for synthesis of nucleotides, proteins, and lipids. In cancers, oncogenic mutations involving growth factor signaling pathways and other key factors such as MYC deregulate these metabolic pathways, an alteration known as the Warburg effect.
Once established, tumors evolve genetically during their outgrowth and progression under the pressure of Darwinian selection.
By the time tumors come to clinical attention (usually 1 gram, 109 cells), has undergone a minimum of 30 cell doublings (likely a substantial underestimation).
Tumors become more aggressive over time (i.e. tumor progression).
Selection of the fittest can explain not only the natural history of cancer, but also changes in tumor behavior following therapy.
In addition to DNA mutations, epigenetic aberrations also contribute to malignant properties: DNA methylation silences gene expression, histone modification can enhance or dampen gene expression
Intrinsic and extrinsic pathways of apoptosis and mechanisms used by tumor cells to evade cell death. (1) Loss of p53, leading to reduced function of pro-apoptotic factors such as BAX. (2) Reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors such as BCL2, BCL-XL, and MCL-1. (3) Loss of apoptotic peptidase activating factor 1 (APAF1). (4) Upregulation of inhibitors of apoptosis (IAP). (5) Reduced CD95 level. (6) Inactivation of death-induced signaling complex. FADD, Fas-associated via death domain.
KEY CONCEPTS: Evasion of Apoptosis
Escape of cells from senescence and mitotic catastrophe caused by telomere shortening. Replication of somatic cells, which do not express telomerase, leads to shortened telomeres. In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence. In the absence of checkpoints, DNA repair pathways, such as the nonhomologous end-joining (NHEJ) pathway are inappropriately activated, leading to the formation of dicentric chromosomes. At mitosis the dicentric chromosomes are pulled apart, generating random double-stranded breaks, which then activate DNA-repair pathways, leading to the random association of double-stranded ends and the formation, again, of dicentric chromosomes. Cells undergo numerous rounds of this bridge-fusion-breakage cycle, which generates massive chromosomal instability and numerous mutations. If cells fail to reexpress telomerase, they eventually undergo mitotic catastrophe and death. Reexpression of telomerase allows the cells to escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis.
Origins of cells with self-renewing capacity in cancer. Cancer stem cells can arise from transformed tissue stem cells (e.g., hematopoietic stem cells in chronic myelogenous leukemia, CML) with intrinsic “stemness” or from proliferating cells that acquire a mutation that confers “stemness” (e.g., granulocyte progenitors in acute promyelocytic leukemia). In both instances, the cancer stem cells undergo asymmetric cell divisions that give rise to committed progenitors that proliferate more rapidly than the cancer stem cells; as a result, most of the malignant cells in both tumors lack self-renewing capacity.
KEY CONCEPTS: Limitless replicative potential
All cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer:
1. Self-sufficiency in growth signals - usually due to oncogene activation
2. Insensitivity to growth-inhibitory signals - Usually because of inactivation of tumor suppressor genes
3. Altered cellular metabolism - (i.e. Warburg effect: tumor cells switch to aerobic glycolysis, enabling macromolecule and organelle synthesis
4. Evasion of apoptosis
5. Limitless replicative potential (immortality) - helps tumor cells avoid cellular senescence and mitotic catastrophe
6. Sustained angiogenesis
7. Ability to invade and metastasize - Due to intrinsic properties of tumor cells and signals initiated by tissue response
8. Ability to evade the host immune response
KEY CONCEPTS: tumor angiogenesis
The metastatic cascade. Sequential steps involved in the hematogenous spread of a tumor.
Sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness and attract inflammatory cells. Proteases secreted from tumor cells and inflammatory cells degrade the basement membrane. Binding of tumor cells to proteolytically generated binding sites and tumor cell migration follow.
Two things that promote tumor cells’ acquisition of genetic and epigenetic alterations that lead to hallmarks of cancer
1. Genomic instability
2. Tumor-associated inflammation
These enable cellular transformation and tumor progression
KEY CONCEPTS: Invasion and metastasis
Oncogene, proto-oncogene, oncoprotein definitions
1. Oncogene: gene that promotes autonomous cell growth in cancer cells
2. Proto-oncogene: unmutated cellular counterparts of oncogenes
3. Oncoprotein: Mutated protein resembling the normal products of proto-oncogenes, whose activity does not depend on external signals
Oncogenes are created by mutations in proto-oncogenes and encode oncoproteins that have the ability to promote cell growth in the absence of normal growth-promoting signals
To aid in understanding the nature and functions of oncoproteins and their role in cancer, it is necessary to briefly describe how normal cells respond to growth factors. Under physiologic conditions, growth factor signaling pathways can be resolved into these 6 steps:
- Binding of a growth factor to its receptor
- Transient and limited activation of growth factor receptor, which activates several cytoplasmic signal-tranducing proteins
- Transmission of the transduced signal to the nucleus via additional cytoplasmic effector proteins and second messengers or by a cascade of signal transduction molecules
- Induction and activation of nuclear regulatory factors that initiate DNA transcription
- Expression of factors that promote entry and progression of the cell into the cell cycle, ultimately resulting in cell division
- Parallel changes in other genes that support cell survival and metabolic alterations needed for optimal growth
Major signaling pathways regulating cellular behavior
- Tyrosine kinase pathway
- G protein-coupled pathway
- JAK/STAT pathway
- WNt pathway
- Notch pathway
- Hedgehog pathway
- TGF-b/SMAD pathway
- NF-kB pathway
Tyrosine kinase pathways are the most frequently mutated in human neoplasms
Proto-oncogenes have multiple roles, but all participate at some level in signaling pathways that drive proliferation (e.g. growth factors, GF receptors, signal transducers, transcription factors, cell cycle components).
Their corresponding oncogenes produce oncoproteins similar to normal counterparts, but are usually constitutively active instead of purely inducable.
As a result of this constitutive activity, pro-growth oncoproteins endow cells with self-sufficiency in growth
Most soluble growth factors act in paracrine fashion. What do neoplastic cells often do instead that is scary?
Autocrine loop: some cancer cells can synthesize the same growth factors to which they’re responsive (i.e. glioblastomas express PDGF and PDGF receptor tyrosine kinases)
Very important oncogenic mutations involving growth factor receptors
1. ERBB1: encodes epidermal growth factor receptor (EGFR) which get point mutations related to cancers (i.e. lung adenocarcinoma). These mutations result in constitutive EGFR tyrosine kinase activation
2. ERBB2: encodes HER2 which is amplified, rather than point mutated, in breast carcinoma. Leads to overexpression of HER2 receptor and constitutive TK activation
3. Gene rearrangements: Activate other receptor tyrosine kinases (i.e. ALK). A deletion in chromosome 5 fuses ALK gene with EML4 gene in lung adenocarcinomas
What is the most important signal transducer and two downstream signaling “arms” involved in the receptor tyrosine kinase signaling pathway?
RAS
MAPK cascade and PI3K / AKT pathway
Colonic polyp.
A, An aedonmatous (glandular) polyp is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk.
B, Gross appearance of several colonic polyps.
This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resemble cartilage.
A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth.
B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.
Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles.
Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor (last card), the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered differentiated because gland formation is seen. The malignant glands have invaded the muscular layer of the colon.
Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow).
Anaplastic tumor showing cellular and nuclear variation in size and shape. The prominent cell in the center field has an abnormal tripolar spindle.
Pleomorphic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells.
A, Carcinoma in situ. A low-power view shows that the epithelium is entirely replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact, and there is no tumor in the subepithelial stroma.
B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface.
Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.
Microscopic view of fibroadenoma of the breast seen in last card. The fibrous capsule (right) delimits the tumor from the surrounding tissue.
Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation.
Low power microscopic view of invasive breast cancer. Note the irregular infiltrative borders without a well-defined capsule and intense stromal reaction.
Colon carcinoma invading pericolonic adipose tissue.
Axillary lymph node with metastatic breast carcinoma. Note the aggregates of tumor cells within the substance of the node and the dilated lymphatic channel.
A liver studded with metastatic cancer.
Microscopic view of lung metastasis. A colonic adenocarcinoma has formed a metastatic nodule in the lung.
KEY CONCEPTS - Characteristics of benign and malignant neoplasms
TABLE - Comparison between benign and malignant tumors
Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of the same origin (leiomyosarcoma).
KEY CONCEPTS - Epidemiology of cancer
Development of a cancer through stepwise acquisition of complementary mutations. The order in which various driver mutations occur in initiated precursor cells is not known and may vary from tumor to tumor.
Tumor evolution. Evolution of a renal cell carcinoma (left panel) and Darwin’s finches (right panel). The renal cell carcinoma evolutionary tree is based on genetic comparisons drawn from sequencing of DNA obtained from different tumor sites; the finch evolutionary tree was surmised by Darwin based on morphologic comparisons of different species of finches on the Galapagos Islands.
Hallmarks of cancer.
TABLE: Selected oncogenes, mode of activation, associated human tumors
Growth factor signaling pathways in cancer. Growth factor receptors, RAS, PI3K, MYC, and D cyclins are oncoproteins that are activated by mutations in various cancers. GAPs apply brakes to RAS activation, and PTEN serves the same function for PI3K.
The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia.
TABLE: Cell cycle components and inhibitors that are frequently mutated in cancer
KEY CONCEPTS: Oncogenes, oncoproteins, and unregulated cell proliferation
TABLE: Selected tumor suppressor genes and associated familial syndromes and cancers
Pathogenesis of retinoblastoma. Two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the sporadic form, both RB mutations in the tumor-founding retinal cell are acquired. In the familial form, all somatic cells inherit one mutated copy of RB gene from a carrier parent, and as a result only one additional RB mutation in a retinal cell is required for complete loss of RB function.
The role of RB in regulating the G1-S checkpoint of the cell cycle. Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin-remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When RB is phosphorylated by the cyclin D-CDK4, cyclin D-CDK6, and cyclin E-CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by cyclin-dependent kinase inhibitors, because they inactivate cyclin-CDK complexes. Virtually all cancer cells show dysregulation of the G1-S checkpoint as a result of mutation in one of four genes that regulate the phosphorylation of RB; these genes are RB, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16). TGF-β, transforming growth factor-β.
KEY CONCEPTS: RB, Governor of the Cell Cycle
The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair by transcriptional upregulation of the cyclin-dependent kinase inhibitor CDKN1A (encoding the cyclin-dependent kinase inhibitor p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of the p53 gene, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
KEY CONCEPTS: p53, Guardian of the Genome
Other tumor suppressor genes
The role of APC in regulating the stability and function of β-catenin. APC and β-catenin are components of the WNT signaling pathway.
A, In resting colonic epithelial cells (not exposed to WNT), β-catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of β-catenin, and intracellular levels of β-catenin are low.
B, When normal colonic epithelial cells are stimulated by WNT molecules, the destruction complex is deactivated, β-catenin degradation does not occur, and cytoplasmic levels increase. β-catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates genes involved in cell cycle progression. C, When APC is mutated or absent, as frequently occurs in colonic polyps and cancers, the destruction of β-catenin cannot occur. β-catenin translocates to the nucleus and coactivates genes that promote entry into the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.
Metabolism and cell growth. Quiescent cells rely mainly on the Krebs cycle for ATP production; if starved, autophagy (self-eating) is induced to provide a source of fuel. When stimulated by growth factors, normal cells markedly upregulate glucose and glutamine uptake, which provide carbon sources for synthesis of nucleotides, proteins, and lipids. In cancers, oncogenic mutations involving growth factor signaling pathways and other key factors such as MYC deregulate these metabolic pathways, an alteration known as the Warburg effect.
Intrinsic and extrinsic pathways of apoptosis and mechanisms used by tumor cells to evade cell death. (1) Loss of p53, leading to reduced function of pro-apoptotic factors such as BAX. (2) Reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors such as BCL2, BCL-XL, and MCL-1. (3) Loss of apoptotic peptidase activating factor 1 (APAF1). (4) Upregulation of inhibitors of apoptosis (IAP). (5) Reduced CD95 level. (6) Inactivation of death-induced signaling complex. FADD, Fas-associated via death domain.
KEY CONCEPTS: Evasion of Apoptosis
Escape of cells from senescence and mitotic catastrophe caused by telomere shortening. Replication of somatic cells, which do not express telomerase, leads to shortened telomeres. In the presence of competent checkpoints, cells undergo arrest and enter nonreplicative senescence. In the absence of checkpoints, DNA repair pathways, such as the nonhomologous end-joining (NHEJ) pathway are inappropriately activated, leading to the formation of dicentric chromosomes. At mitosis the dicentric chromosomes are pulled apart, generating random double-stranded breaks, which then activate DNA-repair pathways, leading to the random association of double-stranded ends and the formation, again, of dicentric chromosomes. Cells undergo numerous rounds of this bridge-fusion-breakage cycle, which generates massive chromosomal instability and numerous mutations. If cells fail to reexpress telomerase, they eventually undergo mitotic catastrophe and death. Reexpression of telomerase allows the cells to escape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis.
Origins of cells with self-renewing capacity in cancer. Cancer stem cells can arise from transformed tissue stem cells (e.g., hematopoietic stem cells in chronic myelogenous leukemia, CML) with intrinsic “stemness” or from proliferating cells that acquire a mutation that confers “stemness” (e.g., granulocyte progenitors in acute promyelocytic leukemia). In both instances, the cancer stem cells undergo asymmetric cell divisions that give rise to committed progenitors that proliferate more rapidly than the cancer stem cells; as a result, most of the malignant cells in both tumors lack self-renewing capacity.
KEY CONCEPTS: Limitless replicative potential
KEY CONCEPTS: tumor angiogenesis
The metastatic cascade. Sequential steps involved in the hematogenous spread of a tumor.
Sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness and attract inflammatory cells. Proteases secreted from tumor cells and inflammatory cells degrade the basement membrane. Binding of tumor cells to proteolytically generated binding sites and tumor cell migration follow.
KEY CONCEPTS: Invasion and metastasis
