Path Book: Chapter 5 Neoplasia pg. 201-213

Question 1

What is the only retrovirus that has been demonstrated to cause cancer in humans?

Answer 1

human T cell lymphotropic virus-1 (HTLV-1)

Question 2

What does HTLV-1 cause in humans?

Answer 2

A form of T cell leukemia/lymphoma. More common in Japan than US.

Question 3

How does HTLV-1 work? How is it transmitted?

Answer 3

HTLV-1 has tropism for CD4+ T cells, and this subset of T cells is the major target for neoplastic transformation. Human infection requires transmission of infected T cells through sexual intercourse, blood products, or breastfeeding.

Leukemia develops only in about 3% to 5% of infected persons after a long latent period of 20 to 50 years.

Question 4

Does HTLV-1 contain an oncogene prone to mutation?

Answer 4

No, nor does it integrate into cellular genome near a particular oncogene. The long latency between infection and cancer suggests a multi-step mutation cascade

Question 5

What is pX?

Answer 5

retroviral gene in HTLV-1 that contains several the TAX gene. The TAX protein has been shown to be necessary and sufficient for cellular transformation

Question 6

How does TAX induce cellular trnasformation?

Answer 6

1) Interaction with NF-κB, the TAX protein can transactivate the expression of genes that encode cytokines, cytokine receptors, and costimulatory molecules.

This inappropriate gene expression leads to autocrine signaling loops and increased activation of promitogenic signaling cascades.

2) Directly binding to and activating cyclins.
3) Repression of several tumor suppressor genes that control the cell cycle, including CDKN2A/p16 and TP53.

Question 7

How does TAX set up an autocrine loop?

Answer 7

The TAX gene turns on several cytokine genes and their recep- tors (e.g., the interleukins IL-2 and IL-2R and IL-15 and IL-15R), setting up an autocrine system that drives T cell proliferation.

Question 8

What kind of paracrine ability does HTLV-1 have?

Answer 8

Increased production of granulocyte-macrophage colony-stimulating factor stimulates neighboring macrophages to produce other T cell mitogens.

Initially, the T cell proliferation is polyclonal, because the virus infects many cells, but because of TAX-based inactivation of tumor suppressor genes such as TP53, the proliferating T cells are at increased risk for secondary transforming events (mutations), which lead ultimately to the outgrowth of a monoclonal neoplastic T cell population.

Question 9

What types of HPV cause benign squamous papillomas (warts) in humans?

Answer 9

1, 2, 4, and 7

Genital warts have low malignant potential and are also associated with low-risk HPVs, predominantly HPV-6 and HPV-11.

Question 10

High-risk HPVs (e.g., types 16 and 18) cause several cancers, particularly squamous ______.

Answer 10

cell carcinoma of the cervix and anogenital region and oropharynx.

In addition, at least 20% of oropharyngeal cancers, particularly those arising in the tonsils, are associated with HPV.

Question 11

The oncogenic potential of HPV can be related to what?

Answer 11

products of two early viral genes, E6 and E7.

Question 12

What does the E7 protein do?

Answer 12

1) The E7 protein binds to Rb and releases the E2F transcription factors that normally are sequestered by Rb, promoting transcription of cyclin E.

Of interest, E7 protein from high-risk HPV types has a higher affinity for Rb than does E7 from low-risk HPV types.

2) E7 also inactivates p21

Question 13

What does the E6 protein do?

Answer 13

It binds to and mediates the degradation of p53.

By analogy with E7, E6 from high-risk HPV types has a higher affinity for p53 than does E6 from low-risk HPV types.

Question 14

How is HPV different in cancer compared to benign warts?

Answer 14

In benign warts the HPV genome is maintained in a nonintegrated episomal form, while in cancers the HPV genome is randomly integrated into the host genome. Integration interrupts the viral DNA, resulting in overexpression of the oncoproteins E6 and E7.

Furthermore, cells in which the viral genome has integrated show significantly more genomic instability.

Question 15

Does HPV alone cause cancer?

Answer 15

No, infection with HPV itself is not sufficient for carcinogenesis. HPV, in all likelihood, acts in concert with other environmental factors.

However, the primacy of HPV infection in the causation of cervical cancer is attested to by the near-complete protection from this cancer by anti-HPV vaccines.

Question 16

EBV is strongly linked to what cancer?

Answer 16

Burkitt lymphoma (common in others)

also in Hodgkins

Question 17

How does EBV cause B cell proliferation?

Answer 17

EBV uses the complement receptor CD21 on B cells to attach to and infect B cells. In vitro, such infection leads to polyclonal B cell proliferation and generation of B lymphoblastoid cell lines. This occurs via mutation of a viral oncogene called LMP1.

NOTE: Although LMP1 is the primary transforming oncogene in the EBV genome, it is not expressed in EBV- associated Burkitt lymphoma, presumably because it also is one of the major viral antigens recognized by the immune system.

Question 18

What does LMP1 do?

Answer 18

1) activates NFkB and JAK/STAT pathways which mimic B cell activation by the B cell surface molecule CD40.
2) Concurrently, LMP1 prevents apoptosis by activating BCL2. Thus, the virus “borrows” a normal B cell activation pathway to promote its own replication by expanding the pool of cells susceptible to infection.

Question 19

What does EBNA2 do (another EBV-encoded protein)?

Answer 19

transactivates cyclin D and the src family of proto-oncogenes.

Question 20

What is vIL-10?

Answer 20

EBV genome contains a viral cytokine, that was pirated from the host genome. This viral cytokine promotes TH2 class switching and can prevent macrophages and monocytes from activating T cells and killing virally infected cells.

Question 21

How does EBV infection affect an immunocompetent person?

Answer 21

EBV-driven polyclonal B cell proliferation is readily controlled, and the affected patient either remains asymptomatic or experiences a self-limited episode of infectious mononucleosis.

In other words, it will not cause cancer

Question 22

What must EBV do to promote Burkitt? Or cancer in general?

Answer 22

It must evade the immune system.

In regions of the world in which Burkitt lymphoma is endemic, malaria impairs immune competence, allowing sustained B cell proliferation.

Question 23

Infected cells expressing viral antigens such as LMP-1 are kept in check by the immune system. Lymphoma cells may emerge only when what happens?

Answer 23

Translocations (t8:14) activate the MYC oncogene, a consistent feature of this tumor. MYC may substitute for LMP1 signaling, allowing the tumor cells to downregulate LMP1 and evade the immune system.

This makes sense because EBV is only associated with about 20% of Burkitt cases so it cant be dependent on LMP1 to cause disease- it must be dependent on something else, in this case a MYC translocation which is seen in almost all cases

Question 24

What happens in patients with deficient T cell function, including those with HIV and organ transplant recipients?

Answer 24

EBV-infected B cells undergo polyclonal expansion, producing lymphoblastoid-like cells.

Question 25

So is the lymphoma associated with EBV in HIV and transplant recipients the same as those in Burkitt lymphoma?

Answer 25

No, the B lymphoblasts in immunosuppressed patients do express viral antigens, such as LMP-1 (in contrast with Burkitt’s), that can be recognized by T cells.

These potentially lethal proliferations can be subdued if T cell immunity can be restored, as may be achieved by withdrawal of immunosuppressive drugs in transplant recipients.

Question 26

What is another cancer associated with EBV?

Answer 26

The EBV genome is found in all tumors of Nasopharyngeal carcinoma LMP-1 is expressed in the carcinoma cells and, as in B cells, activates the NF-κB pathway.

How EBV enters epithelial cells is unclear, as these cells fail to express the CD21 protein that serves as the EBV receptor in B cells.

Question 27

HBV and HCV are strongly associated with what cancer?

Answer 27

hepatocellular carcinoma.

It is estimated that 70% to 85% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV.

Question 28

T or F. The HBV and HCV genomes contain oncogenes that mutate causing cancer progression of a host

Answer 28

F. Neither HBV nor HCV encode any oncoproteins, and although the HBV DNA is integrated within the human genome, there is no consistent pattern of integration in liver cells.

Question 29

So how do HBV and HCV promote cancer?

Answer 29

The dominant effect seems to be immunologically mediated chronic inflammation with hepatocyte death leading to regeneration and genomic damage.

Although the immune system generally is thought to be protective, in the setting of unresolved chronic inflammation, as occurs in viral hepatitis, the immune response may become maladaptive, promoting tumorigenesis.

Question 30

What other condition has been linked the maladaptive nature of chronic inflammation in cancer formation?

Answer 30

chronic gastritis caused by H. pylori

Question 31

Describe how chronic inflammation promotes cancer formation?

Answer 31

Chronic viral infection leads to the compensatory proliferation of hepatocytes. This regenerative process is aided and abetted by mediators produced by activated immune cells.

The immune cells also produce ROS that are bad.
A key molecular step seems to be activation of the nuclear factor-κB (NF-κB) pathway in hepatocytes caused by mediators derived from the activated immune cells. Activation of the NF-κB pathway within hepatocytes blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations.

The HBV genome contains a gene known as HBx. HBx can directly or indirectly activate a variety of transcription factors and several signal transduction pathways, causing cancer. In addition, viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes. HCV as the HCV core protein which is similar in function

Question 32

H pylori is also associated with what other cancers?

Answer 32

gastric adenocarcinomas and gastric lymphomas.

Question 33

How does H. pylori promote gastric adenocarcinoma formation?

Answer 33

It involves increased epithelial cell proliferation on a background of chronic inflammation. As in viral hepatitis, the inflammatory milieu contains numerous genotoxic agents, such as reactive oxygen species.

The H. pylori genome also contains genes directly implicated in oncogenesis. Strains associated with gastric adenocarcinoma have been shown to contain a “pathogenicity island” that contains cytotoxin-associated A gene (CagA). Although H. pylori is noninvasive, CagA is injected into gastric epithelial cells, where it has a variety of effects, including the initiation of a signaling cascade that mimics unregulated growth factor stimulation.

Question 34

How does H. pylori affect the stoamch on a cellular timeline?

Answer 34

The sequence of histopathologic changes consists of initial development of chronic inflammation/gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer.

Question 35

Does H. pylori infection always lead to cancer?

Answer 35

No, cancer progression takes decades to complete and occurs in only 3% of infected patients.

Question 36

H. pylori is associated with an increased risk for the development of gastric lymphomas. What do the lymphomas arise from?

Answer 36

The gastric lymphomas are of B cell origin, and because the transformed B cells grow in a pattern resembling that of normal mucosa-associated lymphoid tissue (MALT), they also have been referred to as MALT lymphomas.

Question 37

How does H. pylori cause gastric lymphoma?

Answer 37

It is thought that H. pylori infection leads to the activation of H. pylori– reactive T cells, which in turn cause polyclonal B cell proliferation. In time, a monoclonal B cell tumor emerges in the proliferating B cells, perhaps as a result of accumulation of mutations in growth regulatory genes.

In keeping with this model, early in the course of disease, eradication of H. pylori “cures” the lymphoma by removing antigenic stimulus for T cells.

Question 38

Antigens that elicit an immune response have been demonstrated in many experimentally induced tumors and in some human cancers.

Initially, they were broadly classified into two categories based on their patterns of expression:

Answer 38

1) tumor-specific antigens, which are present only on tumor cells and not on any normal cells, and
2) tumor-associated antigens, which are present on tumor cells and also on some normal cells.

The modern classification of tumor antigens is based on their molecular structure and source.

Question 39

Which immune mediator is most important in tumor suppression?

Answer 39

CTLs are responsible for the major immune defense mechanism against tumors.

Question 40

How can unique, non-self antigens arise on tumors?

Answer 40

Unique tumor antigens arise from β-catenin, RAS, p53, and CDK4, for which the encoding genes frequently are mutated in tumors.

Because the mutant genes are present only in tumors, their peptides are expressed only in tumor cells. Since many tumors may carry the same mutation, such antigens are shared by different tumors.

Question 41

In some tumors, antigens identified by host immune systems are actually normal, non-mutated antigens. How do they elicit an immune system then?

Answer 41

overexpression of the normal antigen.

It is possible that if the antigen is normally present in such low amounts, it never was detected during immune development.

Question 42

What is an example where a normal host antigen is over-expressed in a tumor and thus is recognized by host immune systems?

Answer 42

In a subset of human melanomas, tyrosinase, an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas, is overexpressed.

T cells from patients with melanoma recognize peptides derived from tyrosinase, raising the possibility that tyrosinase vaccines may stimulate such responses to melanomas

Question 43

What are cancer-testis antigens?

Answer 43

Encoded by genes that are silent in all normal adult tissues except the testis, and are deregulated in cancer cells— hence their name.

Although the protein is present in the testis, it is not expressed on the cell surface in an antigenic form, because sperm do not express MHC class I molecules. Thus, for all practical purposes, these antigens are tumor-specific.

Question 44

What is an example of a cancer-testis antigen?

Answer 44

The MAGE (melanoma antigen gene) family of genes. Although they are tumor-specific, MAGE antigens are not unique for individual tumors. MAGE-1 is expressed on 37% of melanomas and a variable number of lung, liver, stomach, and esophageal carcinomas. Similar antigens called GAGE, BAGE, and RAGE

Question 45

What are Oncofetal antigens or embryonic antigens?

Answer 45

such as carcino-embryonic antigen (CEA) and alpha fetoprotein, are expressed during embryogenesis but not in normal adult tissues.

Derepression of the genes that encode these antigens causes their re-expression in colon and liver cancers. Antibodies can be raised against these antigens and are useful for detection of oncofetal antigens.

Question 46

T or F. Most human and experimental tumors express higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids.

Answer 46

T, these may be diagnostic markers and targets for therapy.

These altered molecules include gangliosides, blood group antigens, and mucins.

Question 47

Several mucins are of special interest and have been the focus of diagnostic and therapeutic studies. Examples?

Answer 47

1) CA-125 and CA-19-9, expressed on ovarian carcinoma and colorectal cancer respectively, and
2) MUC-1, expressed on breast carcinomas. Unlike many other types of mucins, MUC-1 is an integral membrane protein that normally is expressed only on the apical surface of breast ductal epithelium, a site that is relatively sequestered from the immune system.

In ductal carcinomas of the breast, however, the molecule is expressed in an unpolarized fashion and contains new, tumor-specific car- bohydrate and peptide epitopes. These epitopes induce both antibody and T cell responses in cancer patients and are therefore candidates for tumor vaccines.

Question 48

What are differentiation antigens?

Answer 48

Tumors express molecules that normally are present on the cells of origin. These antigens are called differentiation antigens, because they are specific for particular lineages or differentiation stages of various cell types.

Question 49

Do antibodies play a role in tumor suppression?

Answer 49

Although antibodies can be made against tumors, there is no evidence that they play a protective role under physiologic conditions. Pretty much only T cell mediated.

Question 50

How NK cells involved in tumor cell immunity?

Answer 50

NK cells are lymphocytes that are capable of destroying tumor cells without previous sensitization; they may provide the first line of defense against tumor cells.

Tumors that fail to express MHC class I antigens cannot be recognized by T cells, but these tumors may trigger NK cells because the latter are inhibited by recognition of normal autologous class I molecules. Thus, tumors may downregulate MHC class I molecules to avoid recognition by T cells, which then makes them prime targets for NK cells.

Macrophages are also involved in manners similar to microbes

Question 51

Cancers are drastically more prevalent in immunodeficient individuals. Namely, what kinds?

Answer 51

Of note, most (but not all) of these neoplasms are lymphomas, often lymphomas of activated B cells.

Question 52

What are some mechanisms used by tumors to evade host immune responses?

Answer 52

1) Selective outgrowth of antigen-negative variants. Antigen-negative variants are harder to find and kill.
2) Immunosuppression. For example, TGF-β, secreted in large quantities by many tumors, is a potent immunosuppressant.
3) Antigen masking. Many tumor cells produce a thicker coat of external glycocalyx molecules, such as sialic acid–containing mucopolysaccharides, than normal cells.
4) Downregulation of costimulatory molecules.

Question 53

T or F. Location is crucial in both benign and malignant tumors.

Answer 53

T. Consider the effects of a tumor impinging on adjacent blood supplies, blocking hormone release, etc.

Question 54

What is cachexia?

Answer 54

Many cancer patients suffer progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia—a condition referred to as cachexia.

Question 55

T or F. Cachexia is caused by the nutritional demands of the tumor “stealing” body resources and causing loss of appetite.

Answer 55

F. Although patients with cancer often are anorexic, current evidence indicates that cachexia results from the action of soluble factors such as cytokines produced by the tumor and the host, rather than reduced food intake.

Thus, in patients with cancer, calorie expenditure remains high, and basal metabolic rate is increased, despite reduced food intake.

Question 56

What are two (of several) cachexia causing cytokines and how do they work?

Answer 56

1) TNF suppresses appetite and inhibits the action of lipoprotein lipase, inhibiting the release of free fatty acids from lipoproteins.
2) Proteolysis-inducing factor, causes breakdown of skeletal muscle proteins by the ubiquitin-proteosome pathway

Question 57

How is cachexia treated?

Answer 57

There is no satisfactory treatment for cancer cachexia other than removal of the tumor.

Question 58

What are paraneoplastic syndromes?

Answer 58

Symptom complexes that occur in patients with cancer and that cannot be readily explained by local or distant spread of the tumor or by the elaboration of hormones not indigenous to the tissue of origin of the tumor are referred to as paraneoplastic syndromes.

They appear in 10% to 15% of patients with cancer

Question 59

What are the most common paraneoplastic syndromes?

Answer 59

hypercalcemia, Cushing syndrome, and nonbacterial thrombotic endocarditis (hypercoagulability). Also Kassalbach-Merritt syndrome (spontaneous rupture of a vascular tumor)

the neoplasms most often associated with these and other syndromes are lung and breast cancers and hematologic malignancies.

Question 60

What causes hyper-calcemia in cancer patients?

Answer 60

1) The most important mechanism is the synthesis of a parathyroid hormone–related protein (PTHrP) by tumor cells.
2) TGF-α, a polypeptide factor that activates osteoclasts, and the active form of vitamin D.
3) Widespread osteolytic metastatic disease of bone; Note, however, hypercalcemia resulting from skeletal metastases is not a paraneoplastic syndrome.

Question 61

What is Cushing’s syndrome caused by?

Answer 61

Usually is related to ectopic production of ACTH or ACTH-like polypeptides by cancer cells, as occurs in small cell cancers of the lung.

symptoms: truncal obesity, easy bruising

Not only caused by tumors- common in steroid users

Question 62

How are cancers graded?

Answer 62

The cancer may be classified as grade I, II, III, or IV, in order of increasing anaplasia. Criteria for the individual grades vary with each form of neoplasia. Often descriptions are used instead.

Question 63

What is staging of cancers based on? You are really staging the patient, not the tumor.

Answer 63

1) the size of the primary lesion,
2) its extent of spread to regional lymph nodes, and
3) the presence or absence of metastases

Two systems of staging are the TNM and AJC systems

Question 64

Describe the TNM staging system.

Answer 64

In the TNM system, T1, T2, T3, and T4 describe the increasing size of the primary lesion; N0, N1, N2, and N3 indicate progressively advancing node involvement; and M0 and M1 reflect the absence and presence, respectively, of distant metastases.

Question 65

Describe the AJC staging system.

Answer 65

In the AJC method, the cancers are divided into stages 0 to IV, incorporating the size of primary lesions and the presence of nodal spread and of distant metastases.

Of note, when compared with grading, staging has proved to be of greater clinical value.

Question 66

T or F. Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood cannot be utilized for definitive diagnosis of cancer;

Answer 66

T. however, they can be useful screening tests and in some instances have utility in quantitating the response to therapy or detecting disease recurrence.

Question 67

What is PSA used to screen for?

Answer 67

prostatic adenocarcinoma. Prostatic carcinoma can be suspected when elevated levels of PSA are found in the blood.

Question 68

What is a problem is using PSA?

Answer 68

Although PSA levels often are elevated in cancer, PSA levels also may be elevated in benign prostatic hyperplasia or after a prostate exam.

Furthermore, there is no PSA level that ensures that a patient does not have prostate cancer. Thus, the PSA test suffers from both low sensitivity and low specificity.

Question 69

What is CA-125 used to identify?

Answer 69

ovarian cancer

Question 70

What is CA-19-9 used to identify?

Answer 70

colon or pancreatic cancer

Question 71

What is CA-15-3 used to identify?

Answer 71

breast cancer

Question 72

What is human chorionic gonadotropin used to identify?

Answer 72

tropoblastic tumors, nonseminomatous testicular tumor

Question 73

What is calcitonin used to identify?

Answer 73

medullary carcinoma of the thyroid

Question 74

What is a-fetoprotein used to identify?

Answer 74

liver cell cancer, nonsemimatous germ cell tumors of testis

Question 75

What is carcinoembryonic antigen used to identify?

Answer 75

carcinoma of the colon, pancreas, lung, stomach, and heart cancer

Question 76

What is expression profiling?

Answer 76

can tell you if gene are overexpressed or underexpressed