2. NEOPLASIA (TUMORS)
Definitions
Nomenclature
Biology of Tumor Growth
Epidemiology
Molecular Basis of Cancer
Molecular Basis of Carcinogenesis
Agents (The Usual Suspects)
Host Defense (Tumor Immunity)
Clinical Features of Tumors
3. Defnition of Neoplasia
“A neoplasm is an abnormal mass of tissue, the
growth of which exceeds and is
uncoordinated with that of the normal tissues
and persists in the same excessive manner
after cessation of the stimuli which evoked
the change” - Willis
Genetic changes
Autonomous
Clonal
4. Nomenclature – Benign Tumors
-oma = benign neoplasm (NOT carcin-, sarc-, lymph-,
or melan-)
Mesenchymal tumors (mesodermal derived)
chrondroma: cartilaginous tumor
fibroma: fibrous tumor
osteoma: bone tumor
Epithelial tumor (ecto- or endo- derived)
adenoma: tumor forming glands
papilloma: tumor with finger like projections
papillary cystadenoma: papillary and cystic tumor forming
glands
polyp: a “tumor” that projects above a mucosal surface
8. Nomenclature – Malignant Tumors
Sarcomas: mesenchymal tumor
chrondrosarcoma: cartilaginous tumor
fibrosarcoma: fibrous tumor
osteosarcoma: bone tumor
Carcinomas: epithelial tumors
adenocarcinoma: gland forming tumor
squamous cell carcinoma: squamous differentiation
undifferentiated carcinoma: no differentiation
note: carcinomas can arise from ectoderm,
endoderm, or less likely, mesoderm
9.
10.
11.
12.
13.
14.
Tumors with mixed differentiation
Teratoma
tumor comprised of cells from more than one germ layer
arise from totipotent cells (usually gonads)
benign cystic teratoma of ovary is the most common teratoma
Aberrant differentiation (not true neoplasms)
mixed tumors: e.g. pleomorphic adenoma of salivary gland
carcinosarcoma
Hamartoma: disorganized mass of tissue whose cell types are
indiginous to the site of the lesion, e.g., lung
Choriostoma: ectopic focus of normal tissue (heterotopia),
e.g., pancreas, perhaps endometriosis too
Misnomers
hepatoma: malignant liver tumor
melanoma: malignant skin tumor
seminoma: malignant testicular tumor
lymphoma: malignant tumor of lymphocytes
18. Natural History Of Malignant Tumors
1.
2.
Malignant change in the target
cell, referred to as
transformation
Growth of the transformed cells
3. Local invasion
4.
Distant metastases.
19. Differentiation
Well differentiated neoplasm
Poorly differentiated neoplasm
Resembles mature cells of tissue of origin
Composed of primitive cells with little
differentiation
Undifferentiated or “anaplastic” tumor
Correlation with biologic behavior
Benign tumors are well differentiated
Poorly differentiated malignant tumors usually
have worse prognosis than well differentiated
malignant tumors.
20. If cells LOOK
BAD, they are probably going to BEHAVE BAD
Looking “bad” means NOT looking like the cells they supposedly
arose from!
21. If cells LOOK GOOD, they are probably going to BEHAVE GOOD
Looking “good” means looking like the cells they supposedly arose from!
22.
23. “ANAPLASIA” = CANCER
***Pleomorphism
Size
shape
Abnormal nuclear morphology
***Hyperchromasia
High nuclear cytoplasmic ratio
Chromatin clumping
Prominent nucleoli
Mitoses
Mitotic rate
Location of mitoses
Loss of polarity
24.
25.
Dysplasia
Literally means abnormal growth
Malignant transformation is a multistep process
In dysplasia some but not all of the features of
malignancy are present, microscopically
Dysplasia may develop into malignancy
Uterine cervix
Colon polyps
Graded as low-grade or high-grade, often prompting
different clinical decisions
Dysplasia may NOT develop into malignancy
HIGH grade dysplasia often classified with CIS
26.
27.
28. Tumor Growth Rate
Doubling time of tumor cells
Lengthens as tumor grows
30 doublings (109 cells) = 1 g
(months to years)
10 more doublings (1 kg) = lethal burden
(“)
Fraction of tumor cells in replicative pool
May be only 20% even in rapidly growing tumors
Tumor stem cells
Rate at which tumor cells are shed or lost
Apoptosis
Maturation
Implications for therapy
31. Features of Malignant Tumors
Cellular features
Local
invasion
Capsule
Basement membrane
Metastasis
Unequivocal sign of malignancy
Seeding of body cavities
Lymphatic
Hematogenous
32.
33.
34.
35.
36.
37.
38.
39. Significance of Nodal Mets
Example of breast cancer
Halsted radical mastectomy
Sentinel node biopsy
Prognostic
Number of involved nodes is an important
component of TNM staging system
Therapeutic
Overall risk of recurrence
Extent of nodal involvement
Histologic grade and other considerations
“Adjuvant” chemotherapy
40. Benign vs Malignant Features
Feature
Benign
Malignant
Rate of growth
Progressive but
slow. Mitoses few
and normal
Variable. Mitoses
more frequent and
may be abnormal
Differentiation
Well
differentiated
Some degree of
anaplasia
LOCAL
INVASIO
N
Cohesive growth. Poorly cohesive
Capsule & BM
and
not breached
infiltrative!
Metastasis
Absent
infiltrative!
May occur
41.
42.
43.
44.
45.
46. Geographic & Environmental
Sun exposure
Smoking and alcohol abuse
Body mass
Overweight = 50% increase in cancer
Environmental vs. racial factors
Melanomas 6x incidence New Zealand vs. Iceland
Blacks have low incidence of melanoma, so do normally
pigmented areas like areolae on white people
Japanese immigrants to USA
Viral exposure
Human papilloma virus (HPV) and cervical cancer
Hepatitis B virus (HBV) and liver cancer (Africa, Asia)
Epstein-Barr Virus (EBV) and lymphoma
47. Change In Incidence Of Various Cancers With
Migration From Japan To The United States
48.
Age
Predisposing Factors for Cancer
Most cancers occur in persons ≥ 55 years
Childhood cancers
Genetic predispostion
Familial cancer syndromes
Leukemias & CNS neoplasms
Bone tumors
Early age at onset
Two or more primary relatives with the cancer (“soil” theory)
Multiple or bilateral tumors
Polymorphisms that metabolize procarcinogens, e.g., nitrites
Nonhereditary predisposing conditions
Chronic inflammation?
Precancerous conditions
Chronic ulcerative colitis
Atrophic gastritis of pernicious anemia
Leukoplakia of mucous membranes
Immune collapse?
49. Defnition of Neoplasia
“A neoplasm is an abnormal mass of tissue, the growth
of which exceeds and is uncoordinated with that of
the normal tissues and persists in the same excessive
manner after cessation of the stimuli which evoked
the change” - Willis
Genetic changes
Autonomous
Clonal
50. MOLECULAR BASIS
of CANCER
NON-lethal genetic damage
A tumor is formed by the clonal expansion
of a single precursor cell (monoclonal)
Four classes of normal regulatory genes
PROTO-oncogenes
Oncogenes Oncoproteins
DNA repair genes
Apoptosis genes
Carcinogenesis is a multistep process
51. TRANSFORMATION &
PROGRESSION
Self-sufficiency in growth signals
Insensitivity to growth-inhibiting signals
Evasion of apoptosis
Defects in DNA repair: “Spell checker”
Limitless replicative potential: Telomerase
Angiogenesis
Invasive ability
Metastatic ability
54. ONCOGENES
Are MUTATIONS of NORMAL genes
(PROTO-oncogenes)
Growth Factors
Growth Factor Receptors
Signal Transduction
Proteins (RAS)
Nuclear Regulatory Proteins
Cell Cycle Regulators
Oncogenes code for Oncoproteins
55. Category
PROTOOncogene
Mode of
Activation
Associated Human
Tumor
GFs
PDGF-β chain SIS
Fibroblast
HST-1
growth factors
INT-2
TGFα
HGF
Overexpression Astrocytoma
Osteosarcoma
Overexpression Stomach cancer
Amplification
Bladder cancer
TGFα
Breast cancer
Melanoma
Overexpression Astrocytomas
HGF
Hepatocellular
carcinomas
Overexpression Thyroid cancer
56. Category
PROTOOncogene
Mode of
Activation
Associated Human
Tumor
GF
Receptors
EGF-receptor
family
ERB-B1
(ECFR)
Overexpression
Squamous cell carcinomas of
lung, gliomas
ERB-B2
Amplification
Breast and ovarian cancers
CSF-1 receptor
FMS
Point mutation
Leukemia
Receptor for
neurotrophic
factors
RET
Point mutation
Multiple endocrine neoplasia 2A
and B, familial medullary thyroid
carcinomas
PDGF receptor
PDGF-R
Overexpression
Gliomas
Point mutation
Gastrointestinal stromal tumors
and other soft tissue tumors
Receptor for stem KIT
cell (steel) factor
57. Category
PROTOOncogene
Mode of
Activation
Associated Human
Tumor
Signal
Transduction
Proteins
GTP-binding
Point mutation
Colon, lung, and pancreatic
tumors
H-RAS
Point mutation
Bladder and kidney tumors
N-RAS
Nonreceptor
tyrosine kinase
K-RAS
Point mutation
Melanomas, hematologic
malignancies
ABL
Translocation
Chronic myeloid leukemia
Acute lymphoblastic leukemia
RAS signal
transduction
BRAF
Point mutation
Melanomas
WNT signal
transduction
β-catenin
Point mutation
Hepatoblastomas,
hepatocellular carcinoma
59. MYC
Encodes for transcription factors
Also involved with apoptosis
60. P53 and RAS
p53
Activates DNA repair
proteins
Sentinel of G1/S
transition
Initiates apoptosis
Mutated in more than
50% of all human
cancers
RAS
H, N, K, etc., varieties
Single most common
abnormality of
dominant oncogenes in
human tumors
Present in about 1/3 of
all human cancers
64. DNA REPAIR GENE DEFECTS
DNA repair is like a spell checker
HNPCC (Hereditary Non-Polyposis Colon
Cancer [Lynch]): TGF-β, β-catenin, BAX
Xeroderma Pigmentosum: UV fixing gene
Ataxia Telangiectasia: ATM gene
Bloom Syndrome: defective helicase
Fanconi anemia
65. LIMITLESS REPLICATIVE
POTENTIAL
TELOMERES determine the limited
number of duplications a cell will
have, like a cat with nine lives.
TELOMERASE, present in >90% of
human cancers, changes telomeres so
they will have UNLIMITED
replicative potential
66. TUMOR ANGIOGENESIS
Q: How close to a blood vessel must a cell be?
A: 1-2 mm
Activation of VEGF and FGF-b
Tumor size is regulated (allowed) by
angiogenesis/anti-angiogenesis balance
68. Invasion Factors
Detachment ("loosening up") of
the tumor cells from each other
Attachment to matrix components
Degradation of ECM, e.g.,
collagenase, etc.
Migration of tumor cells
73. Carcinogenesis is “MULTISTEP”
NO single oncogene causes cancer
BOTH several oncogenes AND several
tumor suppressor genes must be involved
Gatekeeper/Caretaker concept
Gatekeepers: ONCOGENES and TUMOR
SUPPRESSOR GENES
Caretakers: DNA REPAIR GENES
Tumor “PROGRESSION”
ANGIOGENESIS
HETEROGENEITY from original single cell
74. Carcinogenesis:
The USUAL (3) Suspects
Initiation/Promotion concept:
BOTH initiators AND promotors are needed
NEITHER can cause cancer by itself
INITIATORS (carcinogens) cause
MUTATIONS
PROMOTORS are NOT carcinogenic by
themselves, and MUST take effect AFTER
initiation, NOT before
PROMOTORS enhance the proliferation of
initiated cells
75.
76. Q: WHO are the usual suspects?
Inflammation?
Teratogenesis?
Immune
Suppression?
Neoplasia?
Mutations?
77. A: The SAME 3 that are
ALWAYS blamed!
1)
Chemicals
2) Radiation
3) Infectious Pathogens
78. CHEMICAL CARCINOGENS:
INITIATORS
“PRO”CARCINOGENS
DIRECT
β-Propiolactone
Dimeth. sulfate
Diepoxybutane
Anticancer drugs
(cyclophosphamide,
chlorambucil,
nitrosoureas, and others)
Acylating Agents
1-Acetyl-imidazole
Dimethylcarbamyl chloride
Polycyclic and Heterocyclic
Aromatic Hydrocarbons
Aromatic Amines, Amides,
Azo Dyes
Natural Plant and Microbial
Products
Aflatoxin B1 Hepatomas
Griseofulvin Antifungal
Cycasin from cycads
Safrole from sassafras
Betel nuts Oral SCC
81. RADIATION CARCINOGENS
UV: BCC, SCC, MM (i.e., all 3)
IONIZING: photons and particulate
Hematopoetic and Thyroid (90%/15yrs) tumors
in fallout victims
Solid tumors either less susceptible or require a
longer latency period than LEUK/LYMPH
BCCs in Therapeutic Radiation
96. TUMOR MARKERS
HORMONES: (Paraneoplastic Syndromes)
“ONCO”FETAL: AFP, CEA
ISOENZYMES: PAP, NSE
PROTEINS: PSA, PSMA (“M” = “membrane”)
GLYCOPROTEINS: CA-125, CA-195, CA-153
MOLECULAR: p53, RAS
NOTE: These SAME substances which can
be measured in the blood, also can be stained
by immunochemical methods in tissue
97. MICRO-ARRAYS
THOUSANDS of genes identified from
tumors give the cells their own identity
and FINGERPRINT and may give
important prognostic information as well
as guidelines for therapy. Some say this
may replace standard histopathologic
identifications of tumors.
What do you think?
Hinweis der Redaktion
Poorly differentiated carcinoma of breast.
Best tumor pics are from the Iowa virtual microscope!
Iowa Histopathology
Outline of topics!
Papillary adenoma of colon. Note the fingerlike projections of the tumor.
Iowa Histopathology
Figure 7-2 Colonic polyp.. Gross appearance of several colonic polyps. Also called adenomas.
Sometimes called tubular adenomas, sometimes adenomatous polyp, sometimes “villous” adenoma.
Colonic polyp. This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk.
This view shows the transition from normal squamous epithelium into invasive carcinoma.
Can you tell by the appearance that the SCC “arose” from the squamous epithelium?
A hallmark of well differentiated squamous cell carcinoma is that the nests of invading cells still attempt to make keratin which then gets deposited in the center of the nests, resulting in a keratin "pearl". A “pearl” in a squamous cell carcinoma qualifies it to be “well” differentiated.
From the Iowa Collection
Another characteristic of a well differentiated squamous cell carcinoma is that it still makes visible intercellular bridges.
Squamous cell carcinomas in which intercellular bridges (i.e., desmosomes, or tonofibrils) can be identified, but NOT pearls are often called “moderately” differentiated.
Adenocarcinoma of colon arising in a case of ulcerative colitis.
Do you think that most adenocarcinomas arise from tissues or organs that are “glandular” themselves? Ans : YES!
Lymph node with undifferentiated large cell carcinoma of the lung. If these epithelial tumor cells formed little circular or tubular structures called “glands”, it might better be termed “adenocarcinoma”. If it showed any attempt at keratin formation, “pearls”, or intercellular bridges between tumor cells, it might best be termed “squamous cell” carcinoma.
From the Iowa collection
Misnomers are often REDUNDANT, to try to correct the misnomer.
Figure 7-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. You do not need a microscope to appreciate this tumor produces both connective tissue as well as epithelial derived elements.
Remember, pure “epithelial” tumors may evoke a fibrous response, such as breast or pancreas or prostate adenocarcinomas, but the connective tissue us regarded as NON-neoplastic.
A microscopic view of a similar tumor shows sebaceous glands, respiratory epithelium, bone, and bone marrow.
Don’t mistake this for a “fibrous reaction” to an epithelial tumor.
Dermoid cyst of ovary (a component of benign cystic teratoma)
Iowa Collection
Another linear process, such as the epics of inflammation or healing.
Can “undifferentiated” also be called very very very very very poorly differentiated? ANS: YES
Why might a “well” differentiated malignance be more difficult to diagnose than a “poorly” differentiated malignancy?
Every time you think you understand the concept of differentiation, guys like Dr. John B. Gurdon and Dr. Shinya Yamanaka come along.
The strong relationship between histology and biologic behavior
The Mormon Tabernacle Choir
Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.
Looking “good” means looking like the cells they supposedly arose from!
Dysplasia means potential PRE-cancer. Anaplasia means cancer. The three words: pleomorphism, hyperchromasia, and increased mitoses, are the three most widely used terms to describe malignant tumors on pathology reports.
Anaplastic large cell carcinoma of lung showing cellular and nuclear variation in size and shape. No differentiation into squamous or glandular epithelium is evident. This is what we mean when we say, it looks “bad”, i.e., pleomorphic, hyperchromatic. This is a classic image of a tumor in which any pathologist would call malignant as a knee jerk reflex after looking at it for one nanosecond, even if it took him 10 minutes to put his key into his car ignition that morning. Ugly and nasty are also two more terms commonly used.
Looking “bad” means NOT looking like the cells they supposedly arose from!
Do you remember from chapter 1 that DYS- was one of the seven -plasia brothers?
Dysplastic cells are also often referred to as “atypical” cells.
This epithelium shows severe dysplasia: Note that dysplastic basal cells characterized by cuboidal shape, high nuclear cytoplasmic ratio, hyperchromatism, mitotic activity, and some loss of orientation to the basement membrane, occupy the lower two thirds of the surface rather than just the basal row of cells. More differentiated cells which occupy the outer third, though still retaining some dysplastic nuclear features have the appearance of maturing squamous cells rather than basal cells, and eventually become flattened on the surface.
Carcinoma in situ: This section shows that the dysplastic basiloid cells go all the way to the surface and never undergo significant differentistion towards more differentiated flattened squamous cells. Note however that the basement membrane is still intact. The torturingly and unnecessary insane pressure to differentiate “severe” dysplasias from carcinomas-in-situ has prompted the various “-IN” classification systems, e.g., CIN-III, VIN-III, PIN-III. Is high grade dysplasia any different from carcinoma-in-situ from a microscopic, behavioral, or medical-legal point of view? Ans: NO!
Does “maturation” or “differentiation” make a cell lose its clonality? Answer: NO
Figure 7-12 Biology of tumor growth. The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already completed a major portion of its life cycle as measured by cell doublings. The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. New subclones arise from the descendants of the original transformed cell, and with progressive growth the tumor mass becomes enriched for those variants that are more adept at evading host defenses and are likely to be more aggressive. (Adapted from Tannock IF: Biology of tumor growth. Hosp Pract 18:81, 1983.)
Figure 7-13 Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion to G0, differentiation, and death. Radiation and chemotherapy work on dividing cells, so the size of the non-proliferative pool is important.
The MORE differentiated a cell is, the less likely it is to multiply.
Some wise ass pathologist my tell you he knows of some benign tumors which metastasize.
Can you imagine this tumor being well defined and/or being “encapsulated”?
Note the sharply demarcated border and a thin capsule in this neoplasm which is composed of both proliferating fibrous stroma (fibro) and glands (adenoma). The tumor is at the right and normal breast is at the left. As shown in this view the fibroadenoma, a benign tumor, is well circumscribed and has a fibrous capsule. This view shows the proliferation of benign appearing fibroblasts (arrows) (i.e. the "fibro" component), and several glands (the "adeno" component).
Can you imagine THIS tumor being well defined and/or being “encapsulated”? ANS: NO
The invasiveness aspect of solid tumors is how “cancer” got its name, i.e., “crab”-like
Invasiveness (aka, “infiltration”) has BOTH gross as well as microscopic connotations.
The fibrous (i.e., “scirrous”) response is NOT considered to be neoplastic , like a teratoma or carcinosarcoma, but a reaction to the neoplasm. This fibrous response is also called desmoplasia.
Adenocarcinoma of the breast. Note that the fibrous stroma of the beast is infiltrated by tumor cells arranged in nests with some gland formation. The dense fibrous stroma results in the tumor having a very firm consistency (scirrhous carcinoma). Every pathologist could look at this image, and instantly know it was carcinoma. You don’t have to zoom in and look at the nuclei, if the glands are growing every which way.
If you did this autopsy, and you were blind, could you still diagnose metastatic disease to the liver? ANS: YES
What if the “nodules” were all tiny and diffuse? Would you suspect cirrhosis instead? YES!
Lymph node with metastatic adenocarcinoma. In this case only a few remnants of normal lymph node tissue are seen. Find them.
In fact, this could even be a PRIMARY with some lymphoid tissue reacting to it, especially if you could not see the unique diagnostic features of a lymph node such as a subcapsular sinus.
Adjuvant chemotherapy in breast cancer reduces the incidence of recurrence and metastasis, but is toxic. Such treatment is not advised when the risk of recurrence is very low. Grade and stage are important prognostic factors, but are being supplemented by newer biologic markers.
Nodal dissections are NOT curative or even therapeutic, they are only PROGNOSTIC!!!!!!
In some tumors, like smooth muscle tumors, counting mitoses may be the main way to differentiate a benign from a malignant process!
“If you want to think od “anaplasia” as DE-differentiation, you can, but remember, differentiation NEVER occurs backwards!
“LOCAL INVASION” is in HUGE ALL CAPS font because it is the single most important differentiating feature.
ALL malignancies can potentially metastasize, but there is at least one common benign condition which is also said to “metastasize”. Can you name it?
Is there an absolute line of difference between benign and malignant? Probably not.
Figure 1 indicates the most common cancers expected to occur in men and women in 2005. Among men, cancers of the prostate, lung and bronchus, and colon and rectum account for more than 56% of all newly diagnosed cancers. Prostate cancer alone accounts for approximately 33% (232,090) of incident cases in men. Based on cases diagnosed between 1995 and 2000, about 90% of these estimated new cases of prostate cancer are expected to be diagnosed at local or regional stages, for which 5-year relative survival approaches 100%.
Cancer INCIDENCE
Cancer DEATH rates
Notice that although there are FIVE bullets on this slide, it really is the THREE USUAL SUSPECTS, isn’t it?
FAT is the biggest factor in the sex-specific, high incidence cancers, i.e., prostate and preast.
Figure 7-25 The change in incidence of various cancers with migration from Japan to the United States provides evidence that the occurrence of cancers is related to components of the environment that differ in the two countries. The incidence of each kind of cancer is expressed as the ratio of the death rate in the population being considered to that in a hypothetical population of California whites with the same age distribution; the death rates for whites are thus defined as 1. The death rates among immigrants and immigrants' sons tend consistently toward California norms. (From Cairns J: The cancer problem. In Readings from Scientific American-Cancer Biology. New York, WH Freeman, 1986, p. 13.)
EPIDEMIOLOGY of cancer
A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation.
The various aspects of “malignant transformation”. Just like cancer itself is a progression of increasingly disturbing processes, so is malignant transformation. These are not necessarily exactly linear events, but close.
Look at these as being factors in growth regulation.
This is a BEAUTIFUL chart! Another way of understanding the development of malignancy in a logical way!
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating Cyclin Dependent Kinase (cdk) enzymes
CDK’s (kinases) are enzymes which PHOSPHORYLATE proteins in preparation for the next phase of the cycle.
G1SG2M is regulated by Cyclins DEAB, respectively, and CDKs 4221, respectively.
Signal transduction is a generic term which refers to any process by which a cell converts one kind of signal or stimulus into another.
Note, in every case, there is a NORMAL gene (proto-oncogene) MUTATED to become an ONCOGENE, ultimately resulting in the expression of as tumor.
Note, in every case, there is a NORMAL gene (proto-oncogene) MUTATED to become an ONCOGENE, ultimately resulting in the expression of as tumor.
Note, in every case, there is a NORMAL gene (proto-oncogene) MUTATED to become an ONCOGENE, ultimately resulting in the expression of as tumor.
Note, in every case, there is a NORMAL gene (proto-oncogene) MUTATED to become an ONCOGENE, ultimately resulting in the expression of as tumor.
Myc (cMyc) codes for a protein that binds to the DNA of other genes. When Myc is mutated, or overexpressed, the protein doesn't bind correctly, and often is a big step in the ultimate production of cancer.
These are the TWO other most important and widely studied genes in cancer.
P53 seems to have a variety of functions, and mutations of this gene have a carcinogenic effect at several levels.
A RAS protein
It would be a good idea to have a familiarity with these genes, recognizing that mutations of them result in cancers.
NOTE: Problems of GROWTH SUPPRESSION, result in GROWTH being UN-regulated.
THESE ARE ALL GROWTH SUPPRESSOR GENES WHICH, WHEN MUTATED, LOSE THEIR NORMAL ABILITY TO SUPPRESS cell crowth!!!
Mutations of genes resulting in EVASION of APOPTOSIS would also be a factor in carcinogenesis, wouldn’t it?
Telomeres are a sequence of repetitive bases at the ends of linear chromosomes that prevent adjacent chromosomes from attaching to each other.
Think about this? If a telomere is interfered with, perhaps by telomerase, it LOSES its ability to limit mitoses!
Think about this too: A tumor could NEVER be more than 1-2 mm, if it did not have the ability to generate blood vessels to feed it? Right? Ans: YES
Another AWESOME diagram! Most important diagrammatic explanation of malignancy I have ever seen.
LinearLinearLinearLinearLinearLinearLinearLinearLinearLinearLinearLinear
FOUR orderly steps of “INVASION” (aka, INFILTRATION, or INVASIVENESS)
It would be wise to remember that these THREE genes are often discussed in the ability of tumors to METASTASIZE.
They are metastatic SUPRESSOR genes. So once again, metastasis, like carcinogenesis, is a LOSS of regulation.
Often the term “gene rearrangement” has been used.
Many/Most leukemias/lymphomas have fairly predictable chromosome translocations.
God help you if you try to memorize this.
There is NO ONE SINGLE UNIFORM explanation as to what causes cancer.
I hope you were not expecting to find it here?
The Initiation/Promotion concept is what we have always know about the cause of cancer. You need TWO things: 2) carcinogens (i.e., initiators) and 2) proliferation (i,.e., promotors)
The concept of initiation and promotion is NOT a new concept. We always knew you needed two things to cause cancer:
Carcinogens, mutators
Factors which normally cause hyperplasia, such as steroid hormones, replicators
You know the drill by now!
Direct carcinogens initiators cause mutations DIRECTLY.
“Pro”-carcinogens initiators are metabolized into substances which are more direct.
A glancing familiarity with all these compounds is a good thing to have.
Having a vague recognition of these substances as being carcinogens would be a good idea.
An initiator might cause the necessary mutations in growth regulating genes, but does not have an effect on cell proliferation.
β-Propiolactone is a disinfectant, DMSO is an awesome solvent, Diepoxybutane is a preservative/textile-linking agent.
As you might suspect, promotors are NOT carcinogenic by themselves, but often are agents of hyperplasia, e.g., steroid hormones.
A “promotor” might cause hyperplasia in cells even without the effect of a carcinogen. You can think of a promotor as a “hyperplastic agent”.
A woman may as: “Will estrogens increase my risk of cancer?”. Estrogens and steroid hormones in general are “promotors”.
ALL THREE common types of skin cancer are related to UV radiation.
The FIVE common viruses associated with cancers should also be in your recollection.
CYTOTOXIC CD8+ T-CELLS are the main eliminators of tumor cells
T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor which interacts with peptide-MHC molecules on the membrane of antigen presenting cells (APC). A second signal, the CO-STIMULATORY signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the T cell.
Was the original name for TNF “cachexin”? Ans: Yes.
Would you suspect PIF would be increased in cancer patients who have experienced weight loss?
So if your patient presents with any of these conditions, should you always suspect an underlying malignancy? Ans: Yes.
Often, the term paraneoplastic syndrome is used synonymously with ectopic endocrine hormone production.
These words could not be seen in a real classroom, but they can be seen in a virtual one!
Which one of these two is more important? This is a CRUCIALLY important question!
The main question in grading is: HOW WELL do the tumor cells look like the NORMAL cells from which they arose?
If they look A LOT like “normal” cells, it is a LOW grade with a GOOD prognosis, but perhaps a TUFF diagnosis.
If they look NOT like “normal” cells, it is a HIGH grade with a BAD prognosis, but perhaps an EASY diagnosis.
Immunohistochemistry (IHC) has become the “magic bullet” of diagnostic surgical pathology, based on the theory that even if you do NOT know what kind of tumor cell you are looking at, if you can identify specific antigens by staining for them, then, you can feel sure you know the cell of origin.
IHC does NOT identify antigens which differentiate benign from malignant, but identify antigens common to certain types of cells!
Yesterday: H&E, blue and red
Today: Immunochemistry, brown
Tomorrow: Arrays, yellow, green, red