Neoplasias A53-A59 Flashcards
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
What are the defining characteristics of neoplastic cells (10)
- Autocrine self maintained growth
- Resistant to apoptosis
- Limitless mitotic capacity/immortalization
- Invasion of local tissue
- Metastasizing to new locations
- Remodelling of metabolic pathways
- Desensitized to gorwth inhibiting signals
- Evasion of the immune system
- Capacity for angiogenesis to supply itself
- Monoclonally originating
Tumors are the 2nd leading cause of death. Cardiovascular diseases are the first.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Exceptions to the terminology
- 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.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Benign
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.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Semi-malignant.
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.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Malignant
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.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Borderline.
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.
A/53. General characteristics of neoplasms (benign, semimalignant, malignant and bordrline neoplasms)
Dsecribe Dysplasia, what structural protein is usually lost preceeding dysplasia.
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
A/54. Classification of neoplasms on histology basis
Basically the terminology listed in the previous topic, what is its origin, and is it classified as benign or malignant.
- Define the origin of the neoplastic cells, Epithelial, Mesenchymal, Mixed, or Teratoma
- What is the degree of differentiation of the cells?
- morphologically?
- expression of fetal proteins?
- Is there Invasion of surrounding tissue?
- Is the Pleomorphism of the cell bodies?
- Is there Anaplasia of the nuclei?
- Are there metastases?
- Are there other Immunostaining markers? Like Estrogen receptor? Philadelphia protein, BCR-ABL fusion?
A/55. Characteristics of neoplasms rate growth
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.
A/56. Invasion and metastasis of neoplasms.
Discuss invasion by the different categories of neoplasms
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)
A/56. Invasion and metastasis of neoplasms
What are the phases and steps of metastasis
Phases one: Invasion of the extracellular matrix.
-
Detachment of tumor cells from adjacent cells.
- Loss of local cell attachments (dysplasia). E-cadherin down-regulation is an early event.
- E-cadherin loss removes cell connections, and removes anti-mitotic signaling.
- If this is occuring in an epithelial cell, this is the EMT, Epithelial to Mesenchymal Transition.
-
Degradation of the ECM
- By direct MMP expression or induction of MMP in surrounding cells by cytokine expression
-
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.
- 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.
- Entering the circulation
- Surviving in the circulation
- Evading the immune system
- Extravasating to a new site
- 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.
A/57. Promotion mechanisms of oncogenes and role in carcinogenesis
define proto-oncogenes
oncogenes
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
- Coding sequence mutations: Causing constituitively active signaling, or resistance to inhibition
- Promotor mutations: increased or constituitive expression of the gene.
-
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.
- 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.
- 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.
A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)
Mechanisms of tumor suppressor inactivation
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.
A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)
RB
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.
A/58. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis (RB, p53, APC)
p53
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.
