THE MAGNITUDE OF THE
THE MAGNITUDE OF THE PROBLEMPROBLEM
Age-Age-the most significant risk factor for cancer the most significant risk factor for cancer overalloverall
-- birth and age 49 years, 1 in 29 men and 1 in 19 women will developbirth and age 49 years, 1 in 29 men and 1 in 19 women will develop cancer;
cancer;
-- for the interval between ages 50 and 59 years, 1 in 15 men and 1 infor the interval between ages 50 and 59 years, 1 in 15 men and 1 in 17 women will develop cancer;
17 women will develop cancer;
-- for the interval between ages 60 and 69 years, 1 in 6 men and 1 infor the interval between ages 60 and 69 years, 1 in 6 men and 1 in 10 women will develop cancer;
10 women will develop cancer;
-- for people age 70 and older, 1 in 3 men and for people age 70 and older, 1 in 3 men and 1 in 4 women will develop1 in 4 women will develop cancer.
cancer. Cancer
Cancer- - is the second leading cause ois the second leading cause of death behind heart diseasef death behind heart disease.. Five leading cancer for Male:
Five leading cancer for Male: 1. 1. prostateprostate 2. 2. lunglung 3. 3. colorectalcolorectal 4. 4. gallbladdergallbladder 5. 5. melanomamelanoma
Five leading cancer for Female: Five leading cancer for Female:
1. 1. breastbreast 2. 2. lunglung 3. 3. colorectalcolorectal 4. 4. endometrialendometrial 5. 5. thyroidthyroid DIAGNOSIS: DIAGNOSIS:
-- the diagnosis of cancer relies most heavily on invasive tissue biopsythe diagnosis of cancer relies most heavily on invasive tissue biopsy and should never be made
and should never be made without obtaining tissue;without obtaining tissue;
-- no noninvasive diagnostic test is sufficient to define a diseaseno noninvasive diagnostic test is sufficient to define a disease process as cancer.
process as cancer.
DEFINING THE EXTENT OF DISEASE AND THE PROGNOSIS DEFINING THE EXTENT OF DISEASE AND THE PROGNOSIS
-- first priority in patient management after the diagnosis of cancer isfirst priority in patient management after the diagnosis of cancer is established and shared with the patient is
established and shared with the patient is
! !
evaluated by a variety of noninvasive and invasive diagnostic tests evaluated by a variety of noninvasive and invasive diagnostic tests and procedures
and procedures !
! is based on physical examination, radiographs,is based on physical examination, radiographs, isotopic scans, computed tomography (CT) scans, and other imaging isotopic scans, computed tomography (CT) scans, and other imaging procedures;
procedures; !
!
a surgical procedure, which might include intraoperative palpation, a surgical procedure, which might include intraoperative palpation, resection of regional lymph nodes and/or tissue adjacent to the resection of regional lymph nodes and/or tissue adjacent to the tumor, and inspection and biopsy of organs commonly involved in tumor, and inspection and biopsy of organs commonly involved in disease spread
disease spread
!
! A second major determinant of A second major determinant of treatment outcome is thetreatment outcome is the
-- is a determinant of how a patient is likely to cope with the physiologicis a determinant of how a patient is likely to cope with the physiologic stresses imposed by the cancer and
stresses imposed by the cancer and its treatmentits treatment
MANAGEMENT OF DISEASE AND TREATMENT COMPLICATIONS MANAGEMENT OF DISEASE AND TREATMENT COMPLICATIONS
-- most common side effects of treatment are nausea and vomiting,most common side effects of treatment are nausea and vomiting, febrile neutropenia and myelosuppression
febrile neutropenia and myelosuppression
-- a critical component of cancer mngt is assessing the response toa critical component of cancer mngt is assessing the response to treatment
treatment !
! aa disappearance of all evidencedisappearance of all evidence of disease
of disease !
! aa
of the perpendicular diameters of all measurable lesions. of the perpendicular diameters of all measurable lesions. !
! is defined as the appearance of any new is defined as the appearance of any new lesion or an increase of >25% in the sum of the products of the lesion or an increase of >25% in the sum of the products of the perpendicular diameters of all measurable lesions (or an perpendicular diameters of all measurable lesions (or an increase of 20% in the sums of the longest diameters by increase of 20% in the sums of the longest diameters by RECIST).
RECIST). !
! Tumor shrinkage or growth that does not meet any of theseTumor shrinkage or growth that does not meet any of these criteria is considered
criteria is considered
to determine the extent of to determine the extent of disease.
disease. Staging
Staging- the process of determining the extent of disease is- the process of determining the extent of disease is
Clinical Clinical
staging-Pathologic staging
Pathologic staging- takes into account information obtained during- takes into account information obtained during
physiologic physiologic reserve of the patient.
reserve of the patient.
complete response
complete response is defined as is defined as
partial response
partial response as >50% reduction in the as >50% reduction in the sum of the productssum of the products
Progressive disease Progressive disease
stable disease. stable disease.
MEDICINE
MEDICINE Dr. Dr. MALLEN)MALLEN)
APPROACH TO THE PATIENT WITH CANCER APPROACH TO THE PATIENT WITH CANCER 15 JANUARY 2018
15 JANUARY 2018
PPRO
» The recognition and treatment of depression are important
components of management.
- diagnosis is likely in a patient with a depressed mood (dysphoria) and/or a loss of interest in pleasure (anhedonia) for at least 2 weeks. - In addition, of the following symptoms are usually present: appetite change, sleep problems, psychomotor retardation or agitation, fatigue, feelings of guilt or worthlessness, inability to concentrate, and suicidal ideation.
SUPPORTIVE CARE
- supportive care is a major determinant of quality of life
a. Pain- 25–50% of patients present with pain at diagnosis, 33% have pain associated with treatment, and 75% have pain with progressive disease.
- ~70% of cases, pain is caused by the tumor itself—by invasion of bone, nerves, blood vessels, or mucous membranes or obstruction of a hollow viscus or duct
cord injury), or to chemotherapy injury (mucositis, peripheral neuropathy, phlebitis, steroid-induced aseptic necrosis of the femoral head).
- 10% of cases, pain is unrelated to cancer or its treatment.
b. Nausea- emesis in the cancer patient is usually caused by chemotherapy
- Three forms of emesis are recognized on the basis of their timing with regard to the noxious insult.
1.
of treatment. 2.
but, when present, usually follows cisplatin administration.
o may be related to bowel inflammation from the therapy and can
be controlled with
3.
chemotherapy and represents a conditioned response to visual and olfactory stimuli previously associated with chemotherapy delivery.
o best strategy for preventing anticipatory emesis is to control
emesis in the early cycles of therapy to prevent the conditioning from taking place.
- A serotonin receptor antagonists are
the most effective drugs against highly emetogenic agents, but they are expensive.
c. Effusions- Pleural effusions due to tumors may or may not contain malignant cells.
- Lung cancer, breast cancer, and lymphomas account for ~75% of malignant pleural effusions.
- Their exudative nature is usually gauged by an effusion/serum protein ratio of !0.5 or an effusion/serum lactate dehydrogenase ratio of!0.6.
-- pericardial window or by stripping the pericardium for symptomatic pericardial effusion
- Malignant ascites is usually treated with repeated paracentesis of small volumes of fluid.
- The major complications are
Nutrition-approach has been to define the threshold for nutritional intervention as
e. Psychosocial support- Patients undergoing treatment experience fear, anxiety, and depression.
- Perhaps the most pervasive and threatening concern is the ever-present fear of relapse (the
f. Death and Dying- most common causes of death in patients with cancer are infection (leading to circulatory failure), respiratory failure, hepatic failure, and renal failure.
three or more
Acute emesis, the most common variety, occurs within 24 h
Delayed emesis occurs 1–7 days after treatment; it is rare,
oral dexamethasone and oral metoclopramide
Anticipatory emesis occurs before administration of
ondansetron andgranisetron
Doxycycline is usually the drug of first choice.
occlusion, leakage, and fluid overload d.
<10 unexplained body weight loss, serum transferrin level <1500 mg/L (150 mg/dL), andserum albumin <34 g/L (3.4 g/dL).
CANCER IS A GENETIC DISEASE
- Cancer arises through a series of somatic alterations in DNA that result in unrestrained cellular proliferation.
- Most of these alterations involve actual sequence changes in DNA (i.e., mutations). They may originate as a consequence of random replication errors, exposure to carcinogens (e.g., radiation), or faulty DNA repair processes.
THE CLONAL ORIGIN AND THE MULTI- STEP NATURE OF CANCER - Nearly all cancers originate from a
critical discriminating feature between neoplasia and hyperplasia. - Multiple cumulative mutational events are invariably required for the
progression of a tumor from normal to fully malignant phenotype
TWO TYPES OF CANCER GENES: ONCOGENES AND TUMOR-SUPPRESSOR GENES
1. 2.
!
must be inactivated in cancer. !
cell growth directly, but rather control the ability of the cell to maintain the integrity of its genome.
ONCOGENES IN HUMAN CANCER
MECHANISM OF ONCOGENE ACTIVATION POINT MUTATION
- a common mechanism of oncogene activation. For example, mutations in one of the RAS genes (HRAS, KRAS, or NRAS) are present in up to 85% of pancreatic cancers and 45% of colon cancers
o most of the activated RAS genes contain point mutations in
codons 12, 13, or 61 (these mutations reduce RAS GTPase activity, leading to constitutive activation of the mutant RAS protein).
o
that simply lead to loss of activity. DNA AMPLIFICATION
- this mechanism leads to leading to overexpression of the gene product - increase in DNA copy number may cause cytologically recognizable
chromosome alterations referred to as
(HSRs) if integrated within chromosomes, or double minutes (dmins) if extrachromosomal.
o
amplified DNA sequences of a tumor and had homology to known oncogenes
- Amplification of a cellular gene is often a predictor of poor prognosis
o
cancers and neuroblastoma, respectively. CHROMOSOMAL REARRANGEMENT
- Translocations are particularly common in lymphoid tumors, probably because these cell types have the capability to rearrange their DNA to generate antigen receptors.
o E.g.
reciprocal translocation between chromosomes 8 and 14
- translocation may result in the overexpression of cell cycle regulatory proteins or proteins such as cyclins and of proteins that regulate cell death.
- first reproducible chromosome abnormality detected in human malignancy was the chromosome detected in CML (chr. 9 , 22)" BCR-ABL gene product
CHROMOSOMAL INSTABILITY IN SOLID TUMORS
- Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes referred to as
TUMOR- SUPPRESSOR GENE INACTIVATION IN CANCER
- The normal role of tumor-suppressor genes is to restrain cell growth, and the function of these genes is inactivated in cancer.
- two major types of somatic lesions observed in tumor-suppressor genes during tumor development are
single cell; this clonal origin is a
Oncogenes- comprises genes that positively influence tumor formation Tumor- suppressor genes- negatively impact tumor growth
two-hit hypothesis- states that both copies of a tumor-suppressor gene
caretaker genes- subset of tumor- suppressor genes that do not affect
gain-of-function mutations are less likely to occur than mutations
homogeneous staining regions
NMYC and LMYC- identified through their presence within the
ERBB2/HER2 and NMYC are often amplified in aggressive breast
Burkitt’s lymphoma, a B cell tumor characterized by a
Philadelphia
chromosomal instability (CIN)
point mutations and large
MEDICINE Dr. MALLEN) CANCER GENETICS 15 JANUARY 2018
# LOH- considered a hallmark for the presence of a tumor-suppressor gene at a particular chromosomal location - Gene silencing- another mechanisms of TSG inactivation; an epigenetic
change that leads to the loss of gene expression and occurs in conjunction with hypermethylation of the promoter and histone deacetylation
- Parental imprinting- preferential expression of a particular gene exclusively from the allele contributed by one parent
FAMILIAL CANCER SYNDROMES
- A small fraction of cancers occurs in patients with a genetic predisposition " having a predisposing mutation in one allele of a tumor-suppressor gene
- Tumors of these patients show - Majority are inherited as
- Two types of tumor-suppressor genes:
a. The growth of tumors,
b. The , which, when mutated, lead to genetic instability and therefore act indirectly on tumor growth.
same pathway), a colorectal tumor simply cannot form.
o
colon cancer syndrome due to germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene on chromosome 5.
o
but instead develop only one or a small number of adenomas that rapidly progress to cancer
# due to mutations in one of four DNA mismatch repair genes # Germline mutations in
90% of HNPCC cases, whereas mutations in MSH6 and PMS2 are much less frequent.
loss-of-function
loss of the remaining normal allele autosomal dominant traits
gatekeepers, which directly regulate the caretakers
Familial adenomatous polyposis (FAP) is a dominantly inherited
HNPCC, or Lynch’s syndrome do not develop multiple polyposis,
CANCER CELL BIOLOGY
- Cancers are characterized by unregulated cell division, avoidance of cell death, tissue invasion, and the ability to metastasize
-invasion.
-invasion
- Cancers are named based on their
o epithelial tissue" carcinomas, o mesenchymal tissues" sarcomas,
o hematopoietic tissue "leukemias, lymphomas, and plasma cell
dyscrasias (including multiple myeloma).
- Cancers nearly always ,
the vast majority of which begin in a single cell and therefore are monoclonal in origin
- most cancers are characterized by marked in the populations of cells
o this significantly complicates the treatment of most cancers
because it is likely that there are subsets of cells that will be resistant to therapy
- vast majority of human cancers are characterized by a
contributes to the loss of control of cell proliferation and differentiation and the acquisition of capabilities, such as tissue invasion, the ability to metastasize, and angiogenesis
CELL CYCLE CHECK POINTS
- The progression of a cell through the cell division cycle is regulated at a number of checkpoints by a wide array of genes
At thefirst phase, G1, preparations are made to replicate the genetic material
<< cell stops for check point>>
S phase for DNA synthesis
» The main brake on the process is the
» Once the cell is prepared to move, sequential activation of
cyclin-dependent kinases (CDKs) results in the inactivation of the brake, Rb, by phosphorylation"E2F/DP1, and genes required for S phase
progression are expressed
» If the cell determines that it is unready to move ahead with DNA
<< cell stops for check point>>
» When DNA damage is detected, the p53 pathway is normally
activated
$ p53 gene- the guardian of the genome; it is a transcription factor that is normally present in the cell in very low levels
o p53 is bound tomdm2, a ubiquitin ligase, that both inhibits
p53 transcriptional activation and also targets p53 for degradation in the proteasome.
o damage is sensed, the ATM (ataxia-telangiectasia mutated)
pathway is activated" ATM phosphorylates mdm2, which no longer binds to p53" p53 then stops cell cycle progression, directs the synthesis of repair enzymes, or if the damage is too great, initiates apoptosis of the cell to prevent the propagation of a damaged cell
o a second method of activating p53 gene is the induction of
p14ARF by hyperproliferative signals from oncogenes. p14ARF competes with p53 for binding to mdm2, allowing p53 to escape the effects of mdm2 and accumulate in the cell"Then p53 stops cell cycle progression by activating CDK inhibitors such as p21 and/or initiating the apoptosis pathway.
o Some environmental exposures produce signature mutations
in p53; for example,aflatoxin exposure leads to mutation of arginine to serine at codon 249 and leads to
hepatocellular carcinoma
! most cancers have mutations that .
o This mutation is underscored by the neoplastic transformation
mechanism of human papillomavirus. benign when it grows in an unregulated fashion without tissue
malignant neoplasms- presence of unregulated growth and tissue
origin:
arise as a consequence of genetic alterations
heterogeneity
multiple-step process involving many genetic abnormalities, each of which
retinoblastoma protein, Rb
Induction of p53 by the DNA dam age and oncogene checkpoints disable the p53 pathway
MEDICINE Dr. MALLEN) CANCER CELL BIOLOGY 15 JANUARY 2018
CANCER AS AN ORGAN THAT IGNORES ITS NICHE
- fundamental cellular defects that create a malignant neoplasm act at thecellular level
- cancers usually become clinically detectable when a primary mass is at —such a mass consists of about109 cells. - lethal tumor burden is about 1012 to 1013 cells.
- human tumors grow by
every daughter cell produced by a cell division is itself capable of dividing.
o growth fraction of a tumor .
o growth fraction of the first malignant cell is 100%, and by the time
a patient presents for medical care, the growth fraction is 2–3% or less
o a tumor is slowing its own growth over time
# Some cells are hypoxemic and have inadequate supply of nutrients and energy .
# Some have sustained too much genetic damage to complete the cell cycle but have lost the capacity to undergo apoptosis and therefore survive but do not proliferate
play a major role.
- The proteins that add phosphate groups to proteins are called .
o two major distinct classes of kinases;
a. one class acts on tyrosine residues,
b. the other acts on serine/threonine residues.
o Normally, tyrosine kinase activity is short-lived and reversed by
protein tyrosine phosphatases (PTPs). However, in many human cancers, tyrosine kinases or components of their downstream pathways are activated by mutation, gene amplification, or chromosomal translocations
APOPTOSIS AND OTHER MECHANISMS OF CELL DEATH 1. APOPTOSIS
- A form of programmed cell death - induced by two main pathways:
a. of apoptosis is activated by cross-linking members of the tumor necrosis factor (TNF) receptor superfamily, such as CD95 (Fas) and death receptors DR4 and DR5, by their ligands, Fas ligand or TRAIL (TNF-related apoptosis-inducing ligand), respectively.
# induces the association of domain) and
receptors
# Caspase-8 is activated and then cleaves and activates effector caspases-3 and -7, which then target cellular constituents inducing the morphologic appearance characteristic of apoptosis, which pathologists term “karyorrhexis.”
b.
cytochrome c and SMAC from the mitochondrial inter- membrane space in response to a variety of noxious stimuli, including DNA damage, loss of adherence to the extracellular matrix (ECM), oncogene-induced proliferation, and growth factor deprivation. - release of apoptosis-inducing proteins from the mitochondria is
regulated by pro- and antiapoptotic members of the Bcl-2 family. - Antiapoptotic members (e.g., Bcl-2, Bcl-XL, and Mcl-1) associate with
the mitochondrial outer membrane via their carboxyl termini
! Autophagy- degradation of proteins and organelles by lysosomal proteases
# can serve as a homeostatic mechanism to promote survival for the cell by recycling cellular components to provide necessary energy
# appears to play conflicting roles in the development and survival of cancer
! Necrosis- digestion of cellular components and rupturing of the cell membrane
METASTASIS
- Accounts for thevast majority of deaths from solid tumors - three major features of tissue invasion are
! epithelial-mesenchymal transition (EMT)- process by which cells lose their epithelial properties and gain mesenchymal properties
- Malignant cells that metastasize
for unregulated proliferation. least 1 cm in diameter
Gompertzian kinetics—this means that not
declines exponentially with time
phosphorylation and dephosphorylation
kinases
extrinsic pathway
FADD (Fas-associated death procaspase-8 to death domain motifs of the
intrinsic pathway of apoptosis is initiated by the release of
cell adhesion to the basement membrane, local proteolysis of the membrane, and movement of the cell through the rent in the mem brane and the ECM
undergo EMT as an important step in that process but retain the capacity
- Malignant cells that gain access to the circulation must then repeat those steps at a remote site, find a hospitable niche in a foreign tissue, avoid detection by host defenses, and induce the growth of new blood vessels.
- The rate-limiting step for metastasis is the ability for tumor cells to survive and expand in the novel microenvironment of the metastatic site, and multiple host-tumor interactions determine the ultimate outcome
CANCER METABOLISM
- One of the distinguishing characteristics of cancer cells is that they have altered metabolism as compared with normal cells in supporting survival and their high rates of proliferation.
- Many cancer cells use aerobic glycolysis (Warburg effect) to metabolize glucose, leading to increased lactic acid production
- A number of proteins in cancer cells, including CMYC, HIF1, RAS, p53, pRB, and AKT, are all involved in modulating glycolytic processes and controlling the Warburg effect.
- The inefficient utilization of glucose also leads to a need for alternative metabolic pathways for other compounds as well, one of which is glutamine.
o Glutamine is also inefficiently used by cancer cells.
TUMOR MICROENVIRONMENT, ANGIOGENESIS AND IMMUNE INVASION
- complex microenvironment including many other types of cells (e.g., inflammatory cells), ECM, secreted factors (e.g., growth factors), reactive oxygen and nitrogen species, mechanical factors, blood vessels, and lymphatics.
- One of the critical elements of tumor cell proliferation is delivery of oxygen, nutrients, and circulating factors important for growth and survival.
o The diffusion limit for oxygen in tissues is ~100–200!m, and
o The angiogenic switch is a phase in tumor development when the
dynamic balance of pro- and antiangiogenic factors is tipped in favor of vessel formation by the effects of the tumor on its immediate environment.
o Stimuli for tumor angiogenesis include hypoxemia, inflammation,
and genetic lesions in oncogenes or tumor suppressors that alter tumor cell gene expression.
- Tumor vessels:
# Are not normal; they have chaotic architecture and blood flow # Are tortuous, dilated with an uneven diameter, excessive
branching and shunting
# Tumor blood flow is also variable with areas of hypoxemia and acidosis
# Vessel walls have numerous openings, widened interendothelial junctions
# Lack perivascular cells such as pericytes and mooth muscle cells.
MECHANISMS OF TUMOR VESSEL FORMATION - most tumor blood vessels arise by the process of
tumors secrete trophic angiogenic molecules, the most potent being vascular endothelial growth factors (VEGF), that induce the proliferation and migration of host ECs into the tumor.
- Hypoxemia, a key regulator of tumor angiogenesis, causes the transcriptional induction of the gene encoding VEGF.
- VEGF and its receptors are required for embryonic vasculogenesis (development of new blood vessels when none preexist) and normal (wound healing, corpus luteum formation) and pathologic angiogenesis (tumor angiogenesis, inflammatory conditions such as rheumatoid arthritis).
- VEGF-A is a heparin- binding glycoprotein with at least four isoforms
-and survival than normal ECs.
- Although VEGF signaling is a critical initiator of angiogenesis, this is a complex process regulated by additional signaling pathways
- Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) help to recruit these perivascular cells.
sprouting, in which
