Neoplasia Flashcards
What is cancer,what are the characteristics of cancer,state the hallmarks of cancer
The Epi genetic changes may themselves stem from acquired mutations in genes that regulate such modifi cations.
These genetic and epigenetic changes alter the expression or function of key genes that regulate funda mental cellular processes, such as growth, survival, and senescence.
True or false
All tumors are clonal- explain
Darwinian selection also plays a role in the pro gression and recurrence of cancers.
True or false
The genetic alterations that give rise to these hallmarks of cancers are sustained and enabled by the development of genomic instability, adding fuel to the fire.Genomic instability is a characteristic of cancer
What is genomic instability?
• Cancer is a genetic disorder caused by DNA mutations that are acquired spontaneously or induced by environmental insults.
-In addition, cancers frequently show epigenetic changes, such as focal
increases in DNA methylation and alterations in histone modifications, -Thesegeneticalterationsareheritable,beingpassedtodaugh- ter cells upon cell division. As a result, cells harboring these alterations are subject to darwinian selection (survival of the fittest, arguably the most important scientific concept yet conceived), with cells bearing mutations that provide them with growth or survival advantages outcompeting their neighbors and thus coming to dominate the popu lation.
Accumulation of mutations gives rise to a set of properties that have been called hallmarks of cancer. These include (1) selfsufficiency in growth signals whereby the growth of cancers becomes autonomous and is unregulated by physiologic cues; (2) lack of response to growth inhibitory signals that control nonneoplastic cellular proliferations such as hyperplasias; (3) evasion of cell death, allowing cancer cells to survive under conditions that induce apoptosis in normal cells; (4) limitless repli cative potential, thus making cancer cells immortal; (5) development of angiogenesis(will form new blood vessels)to sustain the growth of cancer cells; (6) ability to invade local tissues and spread to distant sites; (7) reprogramming of metabolic pathways—specifically, a switch to aerobic glycolysis even when there is abundant oxygen; and (8) ability to evade the immune system.
The increased tendency for DNA mutations (changes) and other genetic changes to occur during cell division. Genomic instability is caused by defects in certain processes that control the way cells divide
What is neoplasia ,neoplasm
Why are neoplastic cells said to be transformed ,when is a tumor said to be benign or malignant
Neoplasms therefore enjoy a certain degree of autonomy and tend to increase in size regardless of their local environment. True or false
Why isn’t the autonomy of cancer cells complete?
Of note, however, benign tumors can produce more than localized lumps, and sometimes they are responsible for serious disease.
True or false
Neoplasia literally means “new growth.” Neoplastic cells are said to be transformed because they continue to repli cate, apparently oblivious to the regulatory influences that control normal cell growth.
Their autonomy is by no means complete, however. Some neoplasms require endocrine support, and such dependencies sometimes can be exploited therapeutically. All neoplasms depend on the host for their nutrition and blood supply.
a neoplasm often is referred to as a tumor, and the study of tumors is called oncology (from oncos, “tumor,” and logos, “study of”). Among tumors, the division of neoplasms into benign and malig nant categories is based on a judgment of a tumor’s poten tial clinical behavior.
• A tumor is said to be benign when its microscopic and gross characteristics are considered to be relatively inno cent, implying that it will remain localized and is amenable (easily controlled or responsive ) to local surgical removal; the patient generally survives.
• Malignant tumors are collectively referred to as cancers, derived from the Latin word for “crab”—that is, they adhere to any part that they seize in an obstinate manner, similar to a crab’s behavior. Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metasta size) to cause death. Not all cancers pursue so deadly a course. The most aggressive are also some of the most curable, but the designation malignant constitutes a red flag.
What are the basic components of tumors
What is the importance of the non neoplastic stroma
Although the biologic behavior of tumors largely reflects the behavior of the parenchymal cells, there has been a growing realization that stromal cells and neoplastic cells carry on a twoway conversation that influences the growth of the tumor.
True or false
The tumor derived its name from which component?
All tumors, benign and malignant, have two basic com ponents: (1) the parenchyma, made up of transformed or neoplastic cells, and (2) the supporting, hostderived, non neoplastic stroma, made up of connective tissue, blood vessels, and hostderived inflammatory cells.
The paren chyma of the neoplasm largely determines its biologic behavior, and it is this component from which the tumor
derives its name.
The stroma is crucial to the growth of the neoplasm, since it carries the blood supply and provides support for the growth of parenchymal cells.
What is a fibroma and a chondroma
How is The nomenclature of benign epithelial tumors classified?
What is adenoma ,papilloma ,a polyp ,cystadenoma
Polyp is commonly is used for benign tumors, some malignant tumors also may grow as polyps, whereas other polyps (such as nasal polyps) are not neo plastic but inflammatory in origin. True or false
general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises.
A benign tumor arising in fibrous tissue is a fibroma;
a benign cartilaginous tumor is a chondroma.
The nomenclature of benign epithelial tumors is more complex. They are classi fied sometimes on the basis of their microscopic pattern and sometimes on the basis of their macroscopic pattern. Others are classified by their cells of origin.
For instance, the term adenoma is generally applied to benign epithelial neoplasms producing gland patterns and to neoplasms derived from glands but not necessarily exhibiting glandular patterns. A benign epithelial neo plasm arising from renal tubule cells and growing in glandlike patterns is termed an adenoma, as is a mass of benign epithelial cells that produces no glandular patterns but has its origin in the adrenal cortex.
Papillomas are benign epithelial neoplasms, growing on any surface, that produce microscopic or macroscopic fingerlike fronds.
A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure .
Cystadenomas are hollow cystic masses that typically arise in the ovary.
What are sarcomas ,lymphomas
Sarcomas are des ignated by ?
What are carcinomas
Epithelia of the body are derived from all three germ cell layers true or false
Furthermore, meso derm may give rise to carcinomas (epithelial), sarcomas (mesenchymal), and hematolymphoid tumors (leuke mias and lymphomas). True or false
What is a squamous cell carcinomas ,what is a poorly differentiated or undifferentiated carcinoma
Malignant neoplasms arising in “solid” mesenchymal tissues or its derivatives are called sarcomas,
whereas those arising from the mesenchymal cells of the blood are called leukemias or lymphomas.
Sarcomas are des ignated by the cell type of which they are composed, which is presumably their cell of origin.
Thus, a cancer of fibrous tissue origin is a fibrosarcoma, and a malignant neoplasm composed of chondrocytes is a chondrosarcoma.
• While the epithelia of the body are derived from all three germ cell layers, malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin.
Thus, a malignant neoplasm arising in the renal tubular epithelium (mesoderm) is a carcinoma, as are the cancers arising in the skin (ectoderm) and lining epithelium of the gut (endoderm).
• Carcinomas are subdivided further. Carcinomas that grow in a glandular pattern are called adenocarcinomas, and those that produce squamous cells are called squa- mous cell carcinomas. Sometimes the tissue or organ of origin can be identified, as in the designation of renal cell adenocarcinoma. Sometimes the tumor shows little or no differentiation and must be called poorly differenti- ated or undifferentiated carcinoma.
The transformed cells in a neoplasm, whether benign or malignant, often resemble each other, as though all had been derived from a single progenitor, consistent with the monoclonal origin of tumors.
True or false
What are mixed tumors and give an example
Explain the types of mixed tumors
What is a teratoma
Where does it originate from
Germ cells have the capacity to differenti ate into any of the cell types found in the adult body; not surprisingly, therefore, they may give rise to neoplasms that mimic, in helterskelter fashion, bits of bone, epithe lium, muscle, fat, nerve, and other tissues
True or false
What is hamartoma
Oh histopathological examination what is seen ?
What is choristoma
Hamartomas have tradi tionally been considered developmental malformations, but some genetic studies have shown the presence of acquired translocations, suggesting a neoplastic origin. True or false
In some unusual instances, however, the tumor cells undergo divergent differentiation, creating socalled mixed tumors. The best example is mixed tumor of salivary gland. These tumors have obvious epi thelial components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone
All of these diverse elements are thought to derive from epithelial cells or myoepithelial cells, or both, and the preferred designation for these neoplasms is pleomorphic adenoma.
Fibroadenoma of the female breast is another common mixed tumor. This benign tumor contains a mixture of proliferating ductal elements (adenoma) embedded in a loose fibrous tissue (fibroma). Although only the fibrous component is neoplastic, the term fibroad- enoma remains in common usage.
Teratoma is a special type of mixed tumor that contains recognizable mature or immature cells or tissues represen tative of more than one germ cell layer and sometimes all three.
Teratomas originate from totipotential germ cells such as those normally present in the ovary and testis and sometimes abnormally present in sequestered midline embryonic rests.
.
For example, the terms lymphoma, mesothelioma, melanoma, and seminoma are used for malig nant neoplasms. .
There are other instances of confusing terminology:
• Hamartoma is a mass of disorganized tissue indigenous to the particular site.
Histopathologic examination may show a mass of mature but disorganized hepatic cells, blood vessels, and possibly bile ducts within the liver, or a nodule in the lung containing islands of cartilage, bronchi, and blood vessels.
• Choristoma is a congenital anomaly consisting of a heterotopic (heterotopia is the presence of a particular tissue type at a non-physiological site, but usually co-existing with original tissue in its correct anatomical location) rest of cells.
For example, a small nodule of welldeveloped and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine.
This heterotopic rest may be replete with islets of Langerhans and exocrine glands. The designation -oma, connoting a neoplasm, imparts to the heterotopic rest a gravity far beyond its usual trivial significance.
State the name of a benign and malignant tumor that arises from some named tissues or origin,
There are tumors that are only malignant Name them (they’re seven)
Tissue or origin
Composed of One Parenchymal Cell Type
Connective tissue and derivatives:
Fibroma -benign
Fibrosarcoma-malignant
Lipoma-benign
Liposarcoma-malignant
Chondroma-benign
Chondrosarcoma-malignant
Osteoma-benign
Osteogenic sarcoma-malignant
Endothelial and related tissues
Blood vessels-Hemangioma(benign)-Angiosarcoma(malignant)
Lymph vessels-Lymphangioma(benign)-Lymphangiosarcoma(malignant )
Mesothelium-Mesothelioma(malignant )
Brain coverings-Meningioma(benign)- Invasive meningioma(malignant )
Blood cells and related cells
Hematopoietic cells -Leukemias (malignant)
Lymphoid tissue -Lymphomas(malignant)
Muscle
Smooth- Leiomyoma(benign) Leiomyosarcoma (malignant)
Striated -Rhabdomyoma (benign)
Rhabdomyosarcoma(malignant)
Tumors of epithelial origin
Stratified squamous-Squamous cell papilloma(benign)
Squamous cell or epidermoid carcinoma
(Malignant)
Basal cells of skin or adnexa -Basal cell carcinoma(malignant)
Epithelial lining of glands or ducts-Adenoma(benign)
Adenocarcinoma-(malignant)
Papilloma(benign)
Papillary carcinomas(malignant)
Cystadenoma (benign)
Cystadenocarcinoma(malignant)
Respiratory passages-Bronchial adenoma(benign)
Bronchogenic carcinoma
(Malignant)
Renal epithelium-Renal tubular adenoma(benign), Renal cell carcinoma(malignant)
Liver cells-Liver cell adenoma,hepatocelluoar carcinoma
Urinary tract epithelium (transitional) -Urothelial papilloma(benign), Urothelial carcinoma
Placental epithelium-Hydatidiform mole(benign), Choriocarcinoma(malignant)
Testicular epithelium (germ cells) -Seminoma(malignant) Embryonal carcinoma(malignant)
Tumors of melanocytes -Nevus (benign) Malignant melanoma(malignant)
More Than One Neoplastic Cell Type—Mixed Tumors, Usually Derived from One Germ Cell Layer
Salivary glands -Pleomorphic adenoma (mixed tumor salivary gland )
-Malignant mixed tumor of of salivary gland(malignant)
Renal anlage -Wilms tumor(malignant)
More Than One Neoplastic Cell Type Derived from More Than One Germ Cell Layer—Teratogenous:
Totipotential cells in gonads or in embryonic rests
Mature teratoma and dermoid cyst (benign)
Immature teratoma and teratocarcinoma(malignant)
What are four characteristics that differentiate benign and malignant neoplasms
Explain differentiation and anaplasia
What is lipoma and chondroma made up of
benign tumors appear to be genetically “simple,” harboring fewer muta tions than cancers, and genetically stable, changing little in genotype over time.
The latter feature probably explains why benign tumors such as lipomas and leiomyomas transform to malignancies rarely, if at all.
True or false
The more differentiated the tumor cell, the more com pletely it retains the functional capabilities of its normal counterparts.
True or false
It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors, failure of differentiation, rather than dedifferentiation of specialized cells, accounts for their undifferentiated appearance. Recent studies also indicate that in some cases, dedifferentiation of apparently mature cells does occur during carcinogenesis
True or false
Anaplastic cells display what?
What are the characteristics of anaplastic cells?
In welldifferentiated benign tumors, mitoses are usually rare and are of normal configuration. Between the two extremes lie tumors loosely referred to as moderately well differentiated
True or false
What about the Stroma differentiates benign from malignant
Despite exceptions, the more rapidly growing and the more anaplastic a tumor, the less likely it is to have specialized functional activity.true or false
What is dysplasia,where is it usually encountered
What are the characteristics of dysplastic cells?
In dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers, where they normally occur, but may be seen at all levels and even in surface cells. There is considerable architectural anarchy true or false
What is carcinoma in situ
Where are dysplastic changes commonly found
longterm studies of cigarette smokers show that epithelial dysplasia almost invariably antedates the appear ance of cancer, the term dysplasia is not synonymous with cancer; mild to moderate dysplasias that do not involve the entire thickness of the epithelium sometimes regress completely, par- ticularly if inciting causes are removed.
True or false
Cancers of nonendocrine origin may produce socalled ectopic hormones. For example, certain lung carcinomas may produce adrenocor ticotropic hormone (ACTH), parathyroid hormone–like hormone, insulin, glucagon, and others.
True or false
In practice, the determination of benign versus malignant is made with remarkable accuracy using longestablished clinical and anatomic .there are four fundamental features by which benign and malignant tumors can be distinguished: dif- ferentiation and anaplasia, rate of growth, local invasion, and metastasis.
Differentiation and Anaplasia:
Differentiation and anaplasia are characteristics seen only in the parenchymal cells that constitute the transformed elements of neoplasms.
The differentiation of parenchymal tumor cells refers to the extent to which they resemble their normal forebears morphologically and functionally.
• Benign neoplasms are composed of welldifferentiated cells that closely resemble their normal counterparts.
A lipoma is made up of mature fat cells laden with cytoplasmic lipid vacuoles, and a chondroma is made up of mature cartilage cells that synthesize their usual cartilaginous matrix—evidence of morphologic and functional differentiation.
• Malignant neoplasms are characterized by a wide range of parenchymal cell differentiation, from sur prisingly well differentiated to completely undifferentiated. For example, welldifferentiated ade nocarcinomas of the thyroid may contain normal appearing follicles. Such tumors sometimes may be difficult to distinguish from benign proliferations..
The stroma carrying the blood supply is crucial to the growth of tumors but does not aid in the separation of benign from malignant ones. The amount of stromal connective tissue does deter mine, however, the consistency of a neoplasm.
Certain cancers induce a dense, abundant fibrous stroma (desmoplasia), making them hard, socalled scirrhous tumors.
• Malignant neoplasms that are composed of undifferentiated cells are said to be anaplastic. Lack of cellular differen tiation, or anaplasia, is considered a hallmark of malignancy.
The term anaplasia literally means “back ward formation”—implying dedifferentiation, or loss of the structural and functional differentiation of normal cells.
.1.Anaplastic cells display marked pleomorphism (i.e., variation in size and shape) .2.Often the nuclei are extremely hyperchromatic (darkstaining) and large resulting in an increased nucleartocytoplasmic ratio that may approach 1 : 1 instead of the normal 1:4 or 1:6. Giant cells that are considerably larger than their neighbors may be formed and possess either one enormous nucleus or several nuclei.
Anaplastic nuclei are variable and bizarre in size and shape. 3.The chromatin is coarse and clumped, and nucleoli may be of astounding size.
4.More important, mitoses often are numerous and distinctly atypical; anarchic multi ple spindles may produce tripolar or quadripolar mitotic figures .
5.Also, anaplastic cells usually fail to develop recognizable patterns of orientation to one another (i.e., they lose normal polarity). They may grow
in sheets, with total loss of communal structures, such as glands or stratified squamous architecture.
Benign neoplasms and even welldifferenti ated cancers of endocrine glands frequently elaborate the hormones characteristic of their origin. Welldifferentiated squamous cell carcinomas produce keratin.just as welldifferentiated hepatocellular carcinomas secrete bile. In other instances, unanticipated functions emerge. Some cancers may elaborate fetal proteins not produced by comparable cells in the adult.
dysplasia, refers to disorderly but nonneoplastic proliferation. Dysplasia is encountered principally in epi thelial lesions. It is a loss in the uniformity of individual cells and in their architectural orientation. 1.Dysplastic cells exhibit considerable pleomorphism and 2.often possess hyperchro matic nuclei that are abnormally large for the size of the cell. 3.Mitotic figures are more abundant than usual and frequently appear in abnormal locations within the epithe lium.
.. When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer .
Although dysplastic changes often are found adjacent to foci of malignant transforma tion,
Explain rate of growth as a characteristic of the difference between benign and malignant tumors
Give an example of benign tumors that grow rapidly that some cancers
What factors affect the growth of benign tumors
Adeno mas of the pituitary gland locked into the sella turcica
have been observed to shrink suddenly. Presumably, they undergo a wave of necrosis as progressive enlargement compresses their blood supply. True or false
The rate of growth of malignant tumors usually correlates inversely with? Explain this
What are the variations in the growth of malignant tumors
Rapidly growing malig nant tumors often contain central areas of ischemic necro sis, because the tumor blood supply, derived from the host, fails to keep pace with the oxygen needs of the expanding mass of cells.
True or false
Many lines of experimental and clinical evidence document that most if not all cancers take years and sometimes decades to evolve into clinically overt lesions. This is true even of “acute” childhood leukemias, which often initiate during fetal development yet manifest as fullblown cancers years later.
True or false
Most benign tumors grow slowly, and most cancers grow much faster, eventually spreading locally and to distant sites (metastasizing) and causing death. There are many exceptions to this generalization, however, and some benign tumors grow more rapidly than some cancers.
For example, the rate of growth of leiomyomas (benign smooth muscle tumors) of the uterus is influenced by the circulat ing levels of estrogens. They may increase rapidly in size during pregnancy and then cease growing, becoming largely fibrocalcific, after menopause.
Other influences, such as adequacy of blood supply or pressure constraints, also may affect the growth rate of benign tumors.
it generally is true that most benign tumors increase in size slowly over the span of months to years.
their level of differentiation.
In other words, poorly differentiated tumors tend to grow more rapidly than do welldifferentiated tumors.
However, there is wide variation in the rate of growth. Some grow slowly for years and then enter a phase of rapid growth, signifying the emergence of an aggressive subclone of transformed cells. Others grow relatively slowly and steadily; in exceptional instances, growth may come almost to a standstill. Even more exceptionally, some primary tumors (particularly choriocarcinomas) may become totally necrotic, leaving only secondary metastatic implants.
The continued growth and maintenance of many tissues that contain shortlived cells, such as the formed elements of the blood and the epithelial cells of the gastrointestinal tract and skin, require what?
tissue stem cells divide asymmetrically to produce two types of daughter cells . What re the types?
Tissue stem cells are rare and exist in a niche created by support cells, which produce paracrine factors that sustain the stem cells. True or false
Cancers are immortal and have limitless proliferative capacity, indicat ing that like normal tissues, they also must contain cells with “stemlike” properties. True or false
The cancer stem cell hypothesis posits that, in analogy with normal tissues, only a special subset of cells within tumors has the capacity for selfrenewal. True or false
Where do cancer stem cells arise from?
Explain local invasion as a characteristic difference. between benign and malignant
Give an example of how a benign tumor invades locally but doesn’t move and where the capsule formed is derived from
Which is the most reliable feature that distinguishes malignant from benign tumors
SUMMARY
Characteristics of Benign and Malignant Tumors
• Benign and malignant tumors can be distinguished from one another based on the degree of differentiation, rate of growth, local invasiveness, and distant spread.
• Benign tumors resemble the tissue of origin and are well differentiated; malignant tumors are poorly or completely undifferentiated (anaplastic).
• Benign tumors are slow-growing, whereas malignant tumors generally grow faster.
• Benign tumors are well circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade the surrounding normal tissues.
• Benign tumors remain localized to the site of origin, whereas malignant tumors are locally invasive and metas- tasize to distant sites.
True or false
a resident population of tissue stem cells that are longlived and capable of selfrenewal.
—those with limited proliferative potential, which undergo terminal differentiation to form particular tissues, and those that retain stem cell potential.
Cancer stem cells could arise from normal tissue stem cells or from more differentiated cells that, as part of the transformation process, acquire the property of selfrenewal.
Local Invasion
A benign neoplasm remains localized at its site of origin. It does not have the capacity to infiltrate, invade, or metas tasize to distant sites, as do malignant neoplasms.
For example, as adenomas slowly expand, most develop an enclosing fibrous capsule that separates them from the host tissue. This capsule probably is derived from the stroma of the host tissue as the parenchymal cells atrophy under the pressure of the expanding tumor. The stroma of the tumor itself also may contribute to the capsule .Of note, however, not all benign neoplasms are encapsulated. A few benign tumors are neither encapsulated nor discretely defined; such lack of demarcation is particularly likely to be seen in some benign vascular neoplasms of the dermis. These exceptions are pointed out only to emphasize that although encapsulation is the rule in benign tumors, the lack of a capsule does not mean that a tumor is malignant.
Cancers grow by progressive infiltration, invasion, destruc- tion, and penetration of the surrounding tissue .They do not develop welldefined capsules. There are, however, occasional instances in which a slowly growing malignant tumor deceptively appears to be encased by the stroma of the surrounding host tissue, but microscopic examination usually reveals tiny crablike feet penetrating the margin and infiltrating adjacent structures. The infiltrative mode of growth makes it necessary to remove a wide margin of surrounding normal tissue when surgical excision of a malignant tumor is attempted.
Next to the development of metastases, local invasiveness is the most reliable feature that distinguishes malignant from benign tumors.
What is metastasis
More than any other attribute, the property of metastasis identifies a neoplasm as malignant. Not all cancers have equivalent ability to metastasize. Give an example
In general, the more anaplastic and the larger the primary neoplasm, the more likely is metastatic spread, but as with most rules, there are exceptions. What are the exceptions?
What are the three pathways of malignant neoplasm dissemination
When does spreading by seed occur? What is this type of dissemination characteristic of?
Lymphatic spread is more typical of what kind of cancers and hematogenous spread is typical of what kind of cancers
Neoplasms of the central nervous system, such as a medulloblastoma or ependymoma, may penetrate the cerebral ventricles and be carried by the cerebrospinal fluid to reimplant on the men ingeal surfaces, either within the brain or in the spinal cord. True or false
There are numerous interconnections, however, between the lym phatic and vascular systems, so all forms of cancer may disseminate through either or both systems. True or false
The pattern of lymph node involvement depends principally on?
Lung carcinomas arising in the respi ratory passages metastasize first to where then to where?
What is a sentinel lymph node?
How is it identified?
Carcinoma of the breast usually arises in the upper outer quadrant and first spreads to the axillary nodes. However, medial breast lesions may drain through the chest wall to the nodes along the internal mammary artery. Thereafter, in both instances, the supraclavicular and infra clavicular nodes may be seeded. In some cases, the cancer cells seem to traverse the lymphatic channels within the immediately proximate nodes to be trapped in subsequent lymph nodes, producing socalled skip metastases. The cells may traverse all of the lymph nodes ultimately to reach the vascular compartment by way of the thoracic duct. True or false
although enlargement of nodes near a primary neoplasm should arouse concern for metastatic spread, it does not always imply cancerous involvement. True or false
The necrotic products of the neoplasm and tumor antigens often evoke immunologic responses in the nodes, such as?
What is the favored pathway for sarcomas
What are the frequent sites for hematogenous dissemination
As might be expected, arteries are penetrated less readily than are veins. With venous invasion, the bloodborne cells follow the venous flow draining the site of the neoplasm, with tumor cells often stopping in the first capillary bed they encounter.
skeletal muscles, although rich in capillaries, are rarely the site of secondary deposits. True or false
prostatic carcinoma preferentially spreads to bone, bronchogenic carcinomas tend to involve the adre nals and the brain, and neuroblastomas spread to the liver and bones. Cancers arising near the vertebral column often em bolize through the paravertebral plexus;
Certain carcinomas have a propensity to grow within veins. Renal cell carcinoma often invades the renal vein to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart.
True or false
Metastasis
Metastases are secondary implants of a tumor that are discontinuous with the primary tumor and located in remote tissues .
At one extreme are basal cell carcinomas of the skin and most primary tumors of the central nervous system, which are highly invasive locally but rarely metastasize. At the other extreme are osteogenic (bone) sarcomas, which usually have metastasized to the lungs at the time of initial discovery.
Extremely small cancers have been known to metastasize; conversely, some large and ominouslooking lesions may not.
Malignant neoplasms disseminate by one of three path ways: (1) seeding within body cavities, (2) lymphatic spread, or (3) hematogenous spread.
Spread by seeding occurs when neoplasms invade a natural body cavity. This mode of dissemination is particularly characteristic of cancers of the ovary, which often cover the peritoneal sur faces widely. The implants literally may glaze all peritoneal surfaces and yet not invade the underlying tissues.
Lymphatic spread is more typical of carcinomas, whereas hematogenous spread is favored by sarcomas.
the site of the primary neoplasm and the natural pathways of local lymphatic drainage
. the regional bronchial lymph nodes and then to the tracheobronchial and hilar nodes.
A “sentinel lymph node” is the first regional lymph node that receives lymph flow from a primary tumor. It can be identified by injection of blue dyes or radiolabeled tracers near the primary tumor. Biopsy of sentinel lymph nodes allows determination of the extent of spread of tumor and can be used to plan treatment.
hyperplasia of the follicles (lymphadenitis) and proliferation of macro phages in the subcapsular sinuses (sinus histiocytosis). Thus, histopathologic verification of tumor within an enlarged lymph node is required.
Hematogenous spread is the favored pathway for sarco mas, but carcinomas use it as well.
Since all portal area drainage flows to the liver, and all caval blood flows to the lungs, the liver and lungs are the most frequently involved secondary sites in hematogenous dissemina- tion.
What is carcinogenesis
Many cancers arise from nonneoplastic precursor lesions, true or false
Name three phenotypic attributes of malignant neoplastic cells
What is tumor progression
At the molecular level, tumor progression and associated heterogeneity are most likely to result from multiple mutations that accumulate inde pendently in different cells, generating subclones with dif ferent characteristics such as ?
Some of the mutations may be lethal; others may spur cell growth by affecting protooncogenes or cancer suppressor genes. Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their con- stituent cells may be extremely heterogeneous. True or false
During progression, tumor cells are subjected to ?
And give an example
A growing tumor, therefore, tends to be enriched for subclones that “beat the odds” and are adept at survival, growth, invasion, and metastasis.
True or false
What are the two properties of cancers
PROCESS
Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collec tively give rise to the transformed phenotype.
malignant neoplasms have several phenotypic attributes, such as excessive growth, local invasiveness, and the ability to form distant metastases.
Furthermore, it is well established that over a period of time, many tumors become more aggressive and acquire greater malignant potential. This phenomenon is referred to as tumor progression and is not represented simply by an increase in tumor size.
ability to invade, rate of growth, metastatic ability, karyotype, hormonal responsiveness, and susceptibility to antineoplastic drugs.
immune and nonimmune selection pressures.
For example, cells that are highly antigenic are destroyed by host defenses, whereas those with reduced growth factor requirements are positively selected.
Thus, genetic evolution and selection can explain two of the most pernicious properties of cancers: the tendency for cancers to become (1) more aggressive and (2) less responsive to therapy over time.
What are the hallmarks of cancer
ABL which is a cancer associated gene is affected where? What cancer associated gene is commonly mutated
Some, such as TP53, are commonly mutated; others, such as ABL, are affected only in certain leukemias.
the socalled hallmarks of cancer, which together dictate the malignant phenotype. Six of these are :
• Selfsufficiency in growth signals
• Insensitivity to growth inhibitory signals
• Evasion of cell death
• Limitless replicative potential
• Development of sustained angiogenesis
• Ability to invade and metastasize
To this list may be added two “emerging” hallmarks of cancer, reprogramming of energy metabolism and evasion of the immune system, and two enabling characteristics, genomic instability and tumorpromoting inflammation.
. Of note, by convention, gene symbols are italicized but their protein products are not (e.g., RB gene and Rb protein, TP53 and p53, MYC and MYC).
Explain self sufficiency in growth signals
Under normal conditions,cell proliferation occurs in five steps name them
The mechanisms that endow cancer cells with the ability to proliferate can be grouped according to their role in the growth factor–induced signal transduction cascade and cell cycle regulation. True or false
What is paracrine action
Normally, cells that produce the growth factor do not express the cognate receptor. This specificity prevents the formation of positive feedback loops within the same cell.
True or false
Name two ways cancer cells acquire self sufficiency
Give an example
What kind of proteins deliver continuous mitogenic signals to the cells
Name two ways cancer cells affect growth factor or get growth autonomy
How do cancer cells affect downstream mechanism to get growth autonomy
Name the two important signal transduction molecules or oncoproteins
RAS is the most commonly mutated proto oncogene in human tumors. RAS is a member of a family of small G proteins that bind guanosine nucleotides (guanosine triphosphate [GTP] and guanosine diphosphate [GDP]), similar to the larger trimolecular G proteins.
True or false
How does RAS protein work
What prevents Uncontrolled RAS activation
The activated RAS stimulates downstream regulators of proliferation by two distinct pathways that converge on the nucleus and flood it with signals for cell prolifera tion. True or false
that muta tional activation of these “messengers” to the nucleus can mimic the growth promoting effects of activated RAS. True or false
How is the RAS activated
Cancer cells use a number of strategies to drive their pro liferation and become insensitive to normal growth regula tors. Under physiologic conditions, cell proliferation can be readily resolved into the following steps:
- The binding of a growth factor to its specific receptor on the cell membrane
- Transient and limited activation of the growth factor receptor, which in turn activates several signal transducing proteins on the inner leaflet of the plasma membrane
- Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules
- Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription
- Entry and progression of the cell into the cell cycle, resulting ultimately in cell division
Growth Factors
All normal cells require stimulation by growth factors to undergo proliferation. Most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action).
- Many cancer cells acquire growth selfsufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. For example, many glioblastomas secrete plateletderived growth factor (PDGF) and express the PDGF receptor, and many sar comas make both transforming growth factorα (TGFα) and its receptor. Similar autocrine loops are fairly common in many types of cancer.
- Another mechanism by which cancer cells acquire growth selfsufficiency is by interaction with stroma. In some cases, tumor cells send signals to activate normal cells in the supporting stroma, which in turn produce growth factors that promote tumor growth.
Growth Factor Receptors and Non-Receptor
Tyrosine Kinases
1.Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of the growth factor in the environment.
2.overexpression of growth factor receptors, which can render cancer cells hyperresponsive to levels of the growth factor that would not normally trigger proliferation.
By causing mutations in genes that encode various components of the signaling pathways down stream of growth factor receptors. These signaling proteins couple growth factor receptors to their nuclear targets. They receive signals from activated growth factor receptors and transmit them to the nucleus through activation of signal transduction molecules. (Or either through second messengers or through a cascade of phosphorylation )
Two important members in this category are RAS and ABL.
Normal RAS proteins flip back and forth between an excited signaltransmitting state and a quiescent state. RAS proteins are inactive when bound to GDP; stimulation of cells by growth factors such as EGF and PDGF leads to exchange of GDP for GTP and sub sequent conformational changes that generate active RAS .
This excited signalemitting state is shortlived, however, because the intrinsic guanosine triphosphatase (GTPase) activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDPbound state. The GTPase activity of activated RAS protein is magnified dramatically by a family of GTPaseactivating proteins (GAPs), which act as molecular brakes that prevent uncontrolled RAS activation by favoring hydrolysis of GTP to GDP.
The RAS protein most commonly is activated by point mutations in amino acid residues that are either within the GTPbinding pocket or in the enzymatic region essential for GTP hydrolysis. Both kinds of mutations interfere with GTP hydrolysis, which is essential to inactivate RAS. RAS is thus trapped in its activated, GTPbound form, and the cell is forced into a continuously proliferating state.
Explain downstream signal transduction proteins
Downstream Signal-Transducing Proteins
A relatively common mechanism by which cancer cells acquire growth autonomy is mutations in genes that encode various components of the signaling pathways down stream of growth factor receptors. These signaling proteins couple growth factor receptors to their nuclear targets. They receive signals from activated growth factor receptors and transmit them to the nucleus, either through second messengers or through a cascade of phosphorylation and activation of signal transduction molecules. Two important members in this category are RAS and ABL. Each of these is discussed briefly next.
RAS Protein. RAS is the most commonly mutated proto oncogene in human tumors. Indeed, approximately 30% of all human tumors contain mutated versions of the RAS gene, and the frequency is even higher in some specific cancers (e.g., colon and pancreatic adenocarcinomas).
• RAS is a member of a family of small G proteins that bind guanosine nucleotides (guanosine triphosphate [GTP] and guanosine diphosphate [GDP]), similar to the larger trimolecular G proteins.
• Normal RAS proteins flip back and forth between an excited signaltransmitting state and a quiescent state. RAS proteins are inactive when bound to GDP; stimulation of cells by growth factors such as EGF and PDGF leads to exchange of GDP for GTP and sub sequent conformational changes that generate active RAS (Fig. 5–19). This excited signalemitting state is shortlived, however, because the intrinsic guanosine triphosphatase (GTPase) activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDPbound state. The GTPase activity of activated RAS protein is magnified dramatically by a family of GTPaseactivating proteins (GAPs), which act as molecular brakes that prevent uncontrolled RAS activation by favoring hydrolysis of GTP to GDP.
• The activated RAS stimulates downstream regulators of proliferation by two distinct pathways that converge on the nucleus and flood it with signals for cell prolifera tion. While details of the signaling cascades (some of which are illustrated in Fig. 5–19) downstream of RAS are not discussed here, an important point is that muta tional activation of these “messengers” to the nucleus can mimic the growth promoting effects of activated RAS. For example, BRAF, which lies in the socalled RAF/ERK/MAP kinase pathway, is mutated in more than 60% of melanomas. Mutations of PI3 kinase in the PI3K/AKT pathway also occur with high frequency in some tumor types. Indeed, it appears that activating mutations of RAS as well as its downstream signaling molecules are very common in a wide variety of tumors.
The RAS protein most commonly is activated by point mutations in amino acid residues that are either within the GTPbinding pocket or in the enzymatic region essential for GTP hydrolysis. Both kinds of mutations interfere with GTP hydrolysis, which is essential to inactivate RAS. RAS is thus trapped in its activated, GTPbound form, and the cell is forced into a continuously proliferating state.
Explain nuclear transcription factors and cyclins and cyclin dependent kinases
Nuclear Transcription Factors
Ultimately, all signal transduction pathways enter the nucleus and have an impact on a large bank of responder genes that orchestrate the cell’s orderly advance through the mitotic cycle. Indeed, the ultimate consequence of signaling through oncoproteins such as RAS or ABL is inappropriate and continuous stimulation of nuclear tran scription factors that drive the expression of growth promoting genes. Growth autonomy may thus be a consequence of mutations affecting genes that regulate transcription of DNA. A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, function as transcription factors that regulate the
expression of growthpromoting genes, such as cyclins. Of these, the MYC gene is involved most commonly in human tumors.
The MYC protein can either activate or repress the transcription of other genes. Those activated by MYC include several growthpromoting genes, including cyclin dependent kinases (CDKs), whose products drive cells into the cell cycle (discussed next). Genes repressed by MYC include the CDK inhibitors (CDKIs). Thus, dysregulation of MYC promotes tumorigenesis by increasing expression of genes that promote progression through the cell cycle and repressing genes that slow or prevent progression through the cell cycle. MYC also is a key regulator of intermediate metabolism, upregulating genes that promote aerobic gly colysis (the socalled Warburg effect, described later) and the increased utilization of glutamine, two metabolic changes that are hallmarks of cancer cells. Dysregulation of the MYC gene resulting from a t(8;14) translocation occurs in Burkitt lymphoma, a B cell tumor. MYC also is amplified in breast, colon, lung, and many other cancers; the related NMYC and LMYC genes are amplified in neuroblastomas and small cell cancers of lung.
Cyclins and Cyclin-Dependent Kinases
The ultimate outcome of all growthpromoting stimuli is the entry of quiescent cells into the cell cycle. Cancers may become autonomous if the genes that drive the cell cycle become dysregulated by mutations or amplification. Before further consideration of this aspect of carcinogene sis, a brief review of the normal cell cycle is warranted
What happens in a normal cell cycle
What are the alterations in cell cycle proteins in cancer
Normal Cell Cycle
Cell proliferation is a tightly controlled process that involves a large number of molecules and interrelated pathways. The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins. To achieve DNA replication and division, the cell goes through a tightly controlled sequence of events known as the cell cycle. The cell cycle consists of G1 (presynthetic), S (DNA synthesis), G2 (premitotic), and M (mitotic) phases. Quiescent cells that have not entered the cell cycle are in the G0 state. Each cell cycle phase is dependent on the proper activation and completion of the previous ones and the cycle stops at a place at which an essential gene func tion is deficient. Because of its central role in maintaining tissue homeostasis and regulating physiologic growth pro cesses such as regeneration and repair, the cell cycle has multiple checkpoints, particularly during emergence from G0 into G1 and the transition from G1 to S phase.
Cells can enter G1 either from G0 (quiescent cells) or after completing mitosis (continuously replicating cells). Quies cent cells must first go through the transition from G0 to G1, the first decision step, which functions as a gateway to the cell cycle. Cells in G1 progress through the cell cycle and reach a critical stage at the G1S transition, known as a restriction point, a ratelimiting step for replication. On passing this restriction point, normal cells become irrevers ibly committed to DNA replication. The cell cycle is tightly controlled by activators and inhibitors.
• Progression through the cell cycle, particularly at the G1S transition, is regulated by proteins called cyclins, so
called because of the cyclic nature of their production and degradation, and associated enzymes, the cyclin- dependent kinases (CDKs). CDKs acquire catalytic activity by binding to and forming complexes with the cyclins. The orderly progression of cells through the various phases of the cell cycle is orchestrated by CDKs, which are activated by binding to the cyclins.
• TheCDK–cyclincomplexesphosphorylatecrucialtarget proteins that drive the cell through the cell cycle. On completion of this task, cyclin levels decline rapidly. More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs. The cell cycle may thus be seen as a relay race in which each leg is regulated by a distinct set of cyclins: As one set of cyclins leaves the track, the next set takes over (Fig. 5–20). Activated CDKs in these complexes drive the cell cycle by phosphorylat ing proteins that regulate cell cycle transitions. One such protein is the retinoblastoma protein (Rb), discussed later.
• The activity of CDK–cyclin complexes is regulated by CDK inhibitors (CDKIs), which enforce cell cycle
checkpoints. Embedded in the cell cycle are surveillance mechanisms that are geared to sensing damage to DNA and chromosomes. These quality control checks are called checkpoints; they ensure that cells with damaged DNA or chromosomes do not complete replication. The G1S checkpoint monitors the integrity of DNA before DNA replication, whereas the G2M checkpoint checks DNA after replication and monitors whether the cell can safely enter mitosis. When cells sense DNA damage, checkpoint activation delays the cell cycle and triggers DNA repair mechanisms. If DNA damage is too severe to be repaired, the cells are eliminated by apoptosis, or enter a nonreplicative state called senescence, primarily through p53dependent mechanisms, discussed later on. Mutations in genes regulating these checkpoints allow cells with damaged DNA to divide, producing daughter cells carrying mutations.
• There are several families of CDKIs. One family, composed of three proteins called p21 (CDKN1A), p27 (CDKN1B), and p57 (CDKN1C), inhibits the CDKs broadly, whereas the other family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6. The four members of this family—p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D)—are sometimes called INK4 (A to D) proteins.
Alterations in Cell Cycle Control Proteins in Cancer Cells
With this background it is easy to appreciate that muta tions that dysregulate the activity of cyclins and CDKs would favor cell proliferation. Indeed, all cancers appear to have genetic lesions that disable the G1S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types.
• Mishaps increasing the expression of cyclin D or CDK4 seem to be a common event in neoplastic transforma tion. The cyclin D genes are overexpressed in many cancers, including those affecting the breast, esophagus, liver, and a subset of lymphomas and plasma cell tumors. Amplification of the CDK4 gene occurs in melanomas, sarcomas, and glioblastomas. Mutations affecting cyclins B and E and other CDKs also occur, but they are much less frequent than those affecting cyclin CDK4.
• The CDKIs frequently are disabled by mutation or gene silencing in many human malignancies. Germline muta tions of CDKN2A are present in 25% of melanomaprone kindreds. Somatically acquired deletion or inactivation of CDKN2A is seen in 75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of esophageal cancers, and 20% of non–small cell lung carcinomas, soft tissue sar comas, and bladder cancers.
A final consideration of importance in a discussion of growthpromoting signals is that the increased production of oncoproteins does not by itself lead to sustained prolif eration of cancer cells. There are two builtin mechanisms, cell senescence and apoptosis, that oppose oncogene mediated cell growth. As discussed later, genes that regu late these two braking mechanisms must be disabled to allow unopposed action of oncogenes.
