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Flashcards in Neoplasias A53-A59 Deck (17)
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1
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

What are the defining characteristics of neoplastic cells (10)

A
  1. Autocrine self maintained growth
  2. Resistant to apoptosis
  3. Limitless mitotic capacity/immortalization
  4. Invasion of local tissue
  5. Metastasizing to new locations
  6. Remodelling of metabolic pathways
  7. Desensitized to gorwth inhibiting signals
  8. Evasion of the immune system
  9. Capacity for angiogenesis to supply itself
  10. Monoclonally originating

Tumors are the 2nd leading cause of death. Cardiovascular diseases are the first.

2
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Exceptions to the terminology

A
  • Lymphoma
  • Astrocytoma
  • Glioblastoma
  • Mesothelioma
  • Melanoma
  • Seminoma

Nevus = the benign counterpart to a melanoma aka, a mole.

​Are all malignant, ending in just oma

Both Hodgkins and non-Hodgkins lymphomas are malignant.

Glioblastomas are very malginant, while astrocytomas are less so, but can progress to glioblastomas, and the location of the tumor is the major cause of concern, as it may disrupt brain function.

3
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Benign

A

Benign:

  • more differentiated
  • Usually capsulated
  • well defined borders even if non capsulated
  • easily resected
  • not expected to re-occur

-oma suffix indicates it is benign (with exceptions of specifically named cancers). Lipoma, Fibroma, Chondroma, Hemangioma, Meningioma

Adenoma: benign and originated from epithelial tissue forming glandular like structure

OR

originating from glandular structures.

Papilloma: Epithelial benign tumor that produces the finger-like infoldings, cauliflower appearance.

Hemartoma: Non-neoplastic, differentiated cells in the appropriate organ existing in a disorganized way.

Choristoma: Non-neoplastic, a rest of differentiated cells existing in the wrong organ. Pancreas cells in the lung.

4
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Semi-malignant.

A

Semimalignant tumors. Neoplasms that only show some of the features of malignancy:

  • They are locally invasive
  • Re-occur very frequently
  • May be capsulated, but are irrigularly formed, and difficult to resect completely

BUT

  • They are differentiated
  • They rarely metastasize to new regions.
  • Do not have anaplasia

Pleomorphic adenoma of the salivary gland - grow as invasive sheets in the facial tissue and grow around nerves and vessels, so they are very very hard to remove, and frequently re occur.

Basal cell carcinoma - Epithelial basal neoplastic cells are highly proliferative, may spread into the dermis, but remain nodular and encapsulated, and rarely metastasize to new regions.

5
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Malignant

A

Malignant cells:

  • Invade local tissue
  • Metastasize
  • Usually more rapidly growing
  • Less differentiated
  • More pluripotent
  • Are anaplastic

Carcinoma = malignant of epithelial origin: adenocarcinoma, squamous cell carcinoma, renal cell carcinoma, colorectal carcinoma, hepatocellular carcinoma

Sarcoma = of mesenchymal origin: Osteosarcoma, Fibrosarcoma, Chondrosarcoma,

Malignant teratoma: Of germ cell origin, producing cells form more than one germ layer.

6
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Borderline.

A

Borderline: Characters are in between that of borderline and malignant.

  • Are undifferendiated
  • Are anaplastic

BUT

  • Slow rate of growth
  • No local invasion
  • No metastasis.
  • Don’t usually re-occur
  • Unpredictable and may or may not metastasize.

The behavior, benign or malignant, of borderline tumors can’t be predicted by their morphology. Usually don’t metastacize but there aren’t clear predicitive factors indiciating which ones will.

Examples:

ovarian cystadenoma - Serous cell neoplasm on the outside of the ovary. Epetheloid neoplastic cells surrounding a cysts.

Epetheloid hemangioendothelioma.

7
Q

A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)

Dsecribe Dysplasia, what structural protein is usually lost preceeding dysplasia.

A

Dysplasia is the loss of normal cellular structural arrangement

E-Cadherin is a major cell attachment protein that is usually lost at some point early in neoplastic transformation

8
Q

A/54. Classification of neoplasms on histology basis

A

Basically the terminology listed in the previous topic, what is its origin, and is it classified as benign or malignant.

  1. Define the origin of the neoplastic cells, Epithelial, Mesenchymal, Mixed, or Teratoma
  2. What is the degree of differentiation of the cells?
    • morphologically?
    • expression of fetal proteins?
  3. Is there Invasion of surrounding tissue?
  4. Is the Pleomorphism of the cell bodies?
  5. Is there Anaplasia of the nuclei?
  6. Are there metastases?
  7. Are there other Immunostaining markers? Like Estrogen receptor? Philadelphia protein, BCR-ABL fusion?
9
Q

A/55. Characteristics of neoplasms rate growth

A

Usual approximate growth characteristics, of a malignant tumor.

A 10uM diameter tumor, a single cell. Takes 30 divisions (exponential growth) to reach a 1 mg mass of cells, which is *just* detectable by light microscopy.

From 1mg, it only takes 10 divisions to reach 1 Kg, which is near lethality.

The division kinetics of that specific cell/tumor type will dictate how long these divisions take.

Benign, semi-malignant, and borderline are usually slow.

Malignants are usually fast

Two major theories of neoplasm origins:

Monoclonal theory: a single cell produced all of the daughter cells of the neoplasm

Cancer stem cell theory: an undifferentiated, slowly dividing stem cell is undergoing assymetric divisions, generating a self renewing stem cell population as well as a more rapidly dividing neoplasm cell population. The more rapidly dividing cells are killed by chemo while the stem cells are resistant.

Phases of tumor growth: Different cells within a tumor are in different phases.

Proliferative phase: when the cells are dividing and the tumor is growing in size.

Non-proliferative phase: Cells that are post-mitotic, in G0 phase, and are differentiating, as well as cells that are undergoing apoptosis or necrosis within the tumor.

Chemotherapies and Radiation treatments only target the proliferative fraction.

10
Q

A/56. Invasion and metastasis of neoplasms.

Discuss invasion by the different categories of neoplasms

A

Benign tumors have expansive invasion, usually capsulated, which causes compressive damage of the surrounding tissue, and a capsule or pseudocapsule forms.

Malignant tumors have Infiltrative invasion, intermingling with normal cells.

Semi-malignant also have expansive invasion and are capsulated.

Borderline tumors are not infiltrative and remain localized. They have a preserved basement membrane under/around them. (though they may metastasize)

11
Q

A/56. Invasion and metastasis of neoplasms

What are the phases and steps of metastasis

A

Phases one: Invasion of the extracellular matrix.

  1. Detachment of tumor cells from adjacent cells.
    1. Loss of local cell attachments (dysplasia). E-cadherin down-regulation is an early event.
    2. E-cadherin loss removes cell connections, and removes anti-mitotic signaling.
    3. If this is occuring in an epithelial cell, this is the EMT, Epithelial to Mesenchymal Transition.
  2. Degradation of the ECM
    1. By direct MMP expression or induction of MMP in surrounding cells by cytokine expression
  3. Changed expression of ECM binding proteins,
    • Loss of apoptotic singaling in response to ECM detachment
    • Altered ECM binding protein expression to aid in motility and invasion.
  4. Migration through the degraded ECM to a blood vessel, and attachment to the vessel basal lamina *vessel may be vascular or lymphatic

Phase 2 Vascular dessimination and homing of tumor cells.

  1. Entering the circulation
  2. Surviving in the circulation
  3. Evading the immune system
  4. Extravasating to a new site
  5. Surviving in that new site.
  • Sacrcomas typcially travel by hematogenous spread.
  • Carcinomas go by lymphatic spread.
  • Spread by body cavity aka, Spread by Seeding,
    • occurs when the neoplastic cells invade a body cavity.
    • carcinoma pleure, carcinoma peritonei
    • ovarian cancers whill spread over the entire peritoneal surface of organs, but then will not implant into the organs themselves.
    • Spread of CNS cancers through the ventricles, and then implantation into the meninges.
12
Q

A/57. Promotion mechanisms of oncogenes and role in carcinogenesis

define proto-oncogenes

oncogenes

A

Tumor suppressor genes

DNA repair genes

Apoptosis regulating genes

Growth promoting proto-oncogenes: The normal physiological version of a gene, which can promote cancer upon mutation or loss of correct regulation. The are pro-mitotic genes, anti-apoptotic genes, DNA editing genes.

Oncogene: Mutant versions of any of these gene categories that can produce cancer. They are generally dominant mutations, of transcription factors, growth regulating proteins, cell survial proteins, or cell-cell and cell-matrix interaction proteins.

Mechanisms of conversion from proto-oncogene to oncogene

  1. Coding sequence mutations: Causing constituitively active signaling, or resistance to inhibition
  2. Promotor mutations: increased or constituitive expression of the gene.
  3. Translocation: The gene is regulated by a new promoter.
    • 8/14 translocation, the MYC tf becomes regulated by the Ig heavy chain promoter, causing B cell lymphoma.
    • another one between the Ig heavy chain gene and the BCL-2 gene. anti-apoptotic BCL-2 is then regulated like the Ig heavy chain, also causing B cell lymphoma.
  4. Translocation fusion proteins: Generates a new protein, the BCR-ABL gene, the philadelphia translocation, generating a Tyrosine kinase receptor that is not regulated by anything and always active, generating pro-mitotic signals constantly.
  5. Gene amplification: Multiple copies and increased expression of normal genes, (or already mutated oncogenes), causing increased expression and increased effect. HER2 estrogen receptor is amplified in30% of breat cancers. c-myc amplification is common to many cancers.

Lymphoid cell cancers frequently involve translocations, as these cells normally rearrange their genome for immunological purposes.

13
Q

A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)

Mechanisms of tumor suppressor inactivation

A

Mechanisms of tumor suppressor gene inactivation:

  • Deletion, and haploinsufficiency
  • Stop codon mutation (nonsense mutation)
  • Mis-sense mutation which makes it non-functional
  • Epigenetic silencing,
    • promoter methylation,
    • histone modification and regional silencin
  • Transdominant mutation, in which the mutated protein forms a complex with the functional copy, rendering the whole complex nonfunctional
  • Inherited monozygosity, non-functional allele.

Most tumor suppressor genes require homozygous deletions to be oncogenic.

Often involve a point mutation on one allele making it useless, and one large deletion of the other chromosome, removing it entirely.

Heritable deletions/defects: drastically increase cancer likelihood, because then only one gene mutation needs to spontaneously occur.

While the chances of two spontaneous mutations to the same gene are millions of times lower.

14
Q

A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)

RB

A

Retinoblastoma protein:

  • Binds to the E2F transcription factor,
  • Inhibiting cyclin E expresssion.
  • Active Rb is hypo-phosphorylated, and regulates the G1-S transition, the intiating step of mitosis.
  • Hyperphosphorylation of Rb inactivates it, allowing cell cycle progression.
  • Thus, deletions of Rb, or CyclinD activating mutations can lead to Rb hyperphosphorylation, and development of Retinoblastoma.
15
Q

A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)

p53

A

TP53, Tumor suppressor gene TP53, The guardian of the genome, Transcribes p53 protein. More than 70% of all cancers have p53 defects.

p53 induction:

  • Many stressors trigger p53 expression, so if the cell is exposed to damage, p53 will prevent proliferation.
  • Anoxia,
  • Excessive oncoprotein signaling by MYC or RAS,
  • DNA damage, primarily through sensing by the ATM protein.
  • p53 is always expressed, but if there is no damage, it is bound by inhibitory proteins that trigger its rapid degradation, half life 20 minutes.
  • If the cell is damaged, pathways remove these inhibitory proteins, disinhibiting p53 and rapidly increasing its levels in the cell (ready to go in reserve without needing to be transcribed after the damage)

p53 Functions: 4 main ones. Inducing cell cycle arrest, inducing DNA repair enzyme expression, inducing cell senescence, inducing cell apoptosis.

  • Cell cycle arrest in the G1 phase,
    • via p21 gene induction.
    • p21 inhibits several cyclin-CDK complexes, one of which interacts with Rb, keeping it hypophosphrylated and active.
    • and via miRNA induction, miRNAs that inhibit pro-mitotic genes and anti-apoptotic ones.
  • Induces expression of DNA repair genes, mismatch repair, base excision repair etc.
  • If the DNA damage persists, the cell will enter senescence or p53 will induce senescence apoptosis.
  • If it is repaired, and the damage signal are removed, p53 induces expression of its own inhibitor, allowing the cell to get back to its normal state.
16
Q

A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)

APC

A

Adenomatous Polyposis Coli:

  • APC protein is a cytoplasmic inhibitor of beta-catenin signaling
  • It is an essential component of the beta-catenin destruction complex.
  • Wnt receptor activation inhibits the destruction complex, allowing beta-catenin to signal.
  • Thus APC defect allows continuous beta-catenin signaling,
  • beta-catenin strongly promotes cell proliferation, via several downstream transcription factors and cyclins.
  • It is highly active in the GI tract.

Infants with familial APC defects will be born with polyps already present in their colon, and one of them will invariably become malignant in childhood.

APC sporadic mutations are present in more than 70% of sporadic colon cancers.

17
Q

A/59. DNA repair genes and role in carcinogenesis

A

DNA repair enzymes mutations set up the cell for all of the other essential cancerous mutations, and greatly increases risk for all cancers.

Mismatch repair: Fixes single base pair mutations and mis-pairings.

  • Involves MutSalpha and MutSbeta complexes, involving 3 different proteins.
  • Mutations in MSH2, MSH3, MSH6 (MuS Homolog proteins), or in MLH1 (MutL homolog)
  • Defects in any of these proteins inactivates the system.
  • Familial disruption of the mismatch repair system generates:
  • Hereditary non-polyposus colorectal cancer

Nucleotide excision repair: Repairs Thymine Dimers, resulting from UV exposure. Involves several proteins, as it has to excise part of the DNA.

  • Causes Xeroderma Pigmentosum
  • Patients easily develop skin cancers from sun exposure.

Defects in Homologous Recombination repair and Non-homologous End Joining.

  • ATM gene - DNA damage sensing protein kinase that activates p53. and also activates Non-homologous End Joining proteins, NHEJ.
  • BRCA (BReastCAncer) genes 1 and 2.
  • BRCA1 is involved in both hojmologous or non-homologous repair mechanisms.
  • Familial BRCA1 or BRCA2 mutations increase breast cancer risk.
  • BRCA1 mutations also cause increased prostate cancers and ovarian epithlial cancers.
  • BRCA2 is involved in homologous recombination, and people with homozygous BRCA2 mutations have Fanconi anemia, due to marrow insufficiency, and develop leukemias.
  • Mutations to either of these genes produces large scale breaks and aneuploidy, due to the inability to repair large scale deletions by homologous recombination

ATM defect causes lots of spradic neoplasms

BRCA1 and 2 strongly elevate risk for breast, ovarian, stomach, pancreas, and prostate cancers.

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