Approach to the Px with Cancer

THE MAGNITUDE OF THE PROBLEM

!

A second major determinant of treatment outcome is the

-

is a determinant of how a patient is likely to cope with the physiologic

Age- the most significant risk factor for cancer overall

-

-

stresses imposed by the cancer and its treatment

birth and age 49 years, 1 in 29 men and 1 in 19 women will develop cancer;

MANAGEMENT OF DISEASE AND TREATMENT COMPLICATIONS

for the interval between ages 50 and 59 years, 1 in 15 men and 1 in

-

17 women will develop cancer; -

-

for the interval between ages 60 and 69 years, 1 in 6 men and 1 in

most common side effects of treatment are nausea and vomiting, febrile neutropenia and myelosuppression

-

a critical component of cancer mngt is assessing the response to

10 women will develop cancer;

treatment

for people age 70 and older, 1 in 3 men and 1 in 4 women will develop

!

cancer.

a

 is defined as disappearance of all evidence

of disease

Cancer - is the second leading cause of of death behind heart disease. disease.

!

a

 as >50% reduction in the sum of the products

of the perpendicular diameters of all measurable lesions.

Five leading cancer for Male: !

1.

prostate

2.

lung

lesion or an increase of >25% in the sum of the products of the

3.

colorectal

perpendicular diameters of all measurable lesions (or an

4.

gallbladder

increase of 20% in the sums of the longest diameters by

5.

melanoma

RECIST).

Five leading cancer for Female: 1.

breast

2.

lung

3.

colorectal

4.

endometrial

5.

thyroid

!

  is defined as the appearance of any new

Tumor shrinkage or growth that does not meet any of these criteria is considered

DIAGNOSIS:

-

the diagnosis of cancer relies most heavily on invasive tissue biopsy and should never be made without obtaining tissue;

-

no noninvasive diagnostic test is sufficient to define a disease process as cancer.

DEFINING THE EXTENT OF DISEASE AND THE PROGNOSIS

-

first priority in patient management after the diagnosis of cancer is established and shared with the patient is

!

- the process of determining the extent of disease is evaluated by a variety of noninvasive and invasive diagnostic tests and procedures

!

is based on physical examination, radiographs, isotopic scans, computed tomography (CT) scans, and other imaging procedures;

!

- takes into account information obtained during a surgical procedure, which might include intraoperative palpation, resection of regional lymph nodes and/or tissue adjacent to the tumor, and inspection and biopsy of organs commonly involved in disease spread

!

 may occur in a separate procedure or may be done at the time of definitive surgical resection of the primary tumor

!

TNM System- most widely used system of staging

1

-

~20% of cases, pain is related to a surgical or invasive medical procedure, to radiation injury (mucositis, enteritis, or plexus or spinal 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.

, the most common variety, occurs within 24 h of treatment.

2.

 occurs 1–7 days after treatment; it is rare, but, when present, usually follows cisplatin administration.

o

may be related to bowel inflammation from the therapy and can be

controlled

with

3.

  occurs

before

administration

of

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

  and

 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. »

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,

pericardial effusion -

  of the following symptoms are usually

present: appetite change, sleep problems, psychomotor retardation

 is usually the drug of first choice. pericardial window or by stripping the pericardium for symptomatic Malignant ascites is usually treated with repeated paracentesis of small volumes of fluid.

-

or agitation, fatigue, feelings of guilt or worthlessness, inability to

The major complications are Nutrition- approach has been to define the threshold for nutritional

concentrate, and suicidal ideation.

intervention as  level

, serum L (150 mg/dL), and

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

e.

fear, anxiety, and depression. -

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

Psychosocial support- Patients undergoing treatment experience

Perhaps the most pervasive and threatening concern is the everpresent 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.

2

CANCER IS A GENETIC DISEASE

-

-

MECHANISM OF ONCOGENE ACTIVATION

Cancer arises through a series of somatic alterations in DNA that result

POINT MUTATION

in unrestrained cellular proliferation.

-

a common mechanism of oncogene activation. For example, mutations

Most of these alterations involve actual sequence changes in DNA (i.e.,

in one of the RAS genes (HRAS, KRAS, or NRAS) are present in up to

mutations). They may originate as a consequence of random

85% of pancreatic cancers and 45% of colon cancers

replication errors, exposure to carcinogens (e.g., radiation), or faulty

o

DNA repair processes.

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).

THE CLONAL ORIGIN AND THE MULTI- STEP NATURE OF CANCER

-

Nearly all cancers originate from a

; this clonal origin  is a

that simply lead to loss of activity.

critical discriminating feature between neoplasia and hyperplasia. -

Multiple cumulative mutational events  are invariably required for the

DNA AMPLIFICATION

progression of a tumor from normal to fully malignant phenotype

-

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

TWO TYPES OF CANCER GENES: ONCOGENES AND TUMOR-

(HSRs) if integrated within chromosomes, or double minutes (dmins) if

SUPPRESSOR GENES

1.

 are less likely to occur than mutations

o

extrachromosomal.

- comprises genes that positively influence tumor formation

2.

 negatively impact tumor growth

- identified through their presence within the

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  are often amplified in aggressive breast

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.

, a B cell tumor characterized by a

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

!

- states that both copies of a tumor-suppressor gene

Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes referred to as

must be inactivated in cancer. !

TUMOR- SUPPRESSOR GENE INACTIVATION IN CANCER

- subset of tumor- suppressor genes that do not affect

-

cell growth directly, but rather control the ability of the cell to maintain the integrity of its genome.

!

-

have

crucial

roles

in

cell

two major types of somatic lesions observed in tumor-suppressor genes during tumor development are

proliferation

and

differentiation !

and the function of these genes is inactivated in cancer. -

ONCOGENES IN HUMAN CANCER

The normal role of tumor-suppressor genes is to restrain cell growth,

o

otherwise nonfunctional proteins

The normal growth and differentiation of cells is controlled by growth factors that bind to receptors on the surface of the cell.

- frequently lead to truncated protein products or

o

- lead to the loss of a functional product and sometimes encompass the entire gene or even the entire

3

chromosome arm, leading to loss of heterozygosity (LOH) in the

the absence of mutation of this gatekeeper (or a gene acting within the

#

same pathway), a colorectal tumor simply cannot form.

LOH- considered a hallmark for the presence of a tumor-

colon cancer syndrome due to germline mutations in the

change that leads to the loss of gene expression and occurs in

adenomatous polyposis coli (APC) tumor-suppressor gene on

conjunction with hypermethylation of the promoter and histone

chromosome 5.  do not develop multiple polyposis,

o

Parental imprinting - preferential expression of a particular gene

but instead develop only one or a small number of adenomas that

exclusively from the allele contributed by one parent

rapidly progress to cancer

FAMILIAL CANCER SYNDROMES

-

 is a dominantly inherited

o

Gene silencing- another mechanisms of TSG inactivation; an epigenetic

deacetylation -

APC is thus considered to be a gatekeeper for colon tumorigenesis: in

tumor DNA compared to the corresponding normal tissue DNA

suppressor gene at a particular chromosomal location -

-

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:

#

due to mutations in one of four DNA mismatch repair genes

#

Germline mutations in

 account for more than

90% of HNPCC cases, whereas mutations in MSH6 and PMS2 are much less frequent.

 traits

a.

The

, which directly regulate the growth of tumors,

b.

The

, which, when mutated, lead to genetic instability

and therefore act indirectly on tumor growth.

4

>

CANCER CELL BIOLOGY

Cancers are characterized by unregulated cell division, avoidance of

-

cell death, tissue invasion, and the ability to metastasize  -

  when it grows in an unregulated fashion without tissue

»

When DNA damage is detected, the p53 pathway is normally

invasion.

activated

-

- presence of unregulated growth and tissue

$

invasion -

p53 gene- the guardian of the genome; it is a transcription factor that

is normally present in the cell in very low levels

Cancers are named based on their

:

o

o

epithelial tissue " carcinomas,

p53 transcriptional activation and also targets p53 for

o

mesenchymal tissues " sarcomas,

degradation in the proteasome.

o

hematopoietic tissue "leukemias, lymphomas, and plasma cell

o

Cancers nearly always

-

no longer binds to p53 " p53 then stops cell cycle

,

the vast majority of which begin in a single cell  and therefore are

progression, directs the synthesis of repair enzymes, or if

monoclonal in origin

the damage is too great, initiates apoptosis of the cell to

most cancers are characterized by marked

  in the

prevent the propagation of a damaged cell

populations of cells o

-

damage is sensed, the ATM (ataxia-telangiectasia mutated)

pathway is activated " ATM phosphorylates mdm2, which

dyscrasias (including multiple myeloma). -

p53 is bound to mdm2, a ubiquitin ligase, that both inhibits

o

a second method of activating p53 gene is the induction of p14

ARF

 by hyperproliferative signals from oncogenes.

because it is likely that there are subsets of cells that will be

p14

ARF

 competes with p53 for binding to mdm2, allowing

resistant to therapy

p53 to escape the effects of mdm2 and accumulate in the

this significantly complicates the treatment of most cancers

cell "Then p53 stops cell cycle progression by activating

vast majority of human cancers are characterized by a   involving many genetic abnormalities, each of which

CDK inhibitors such as p21 and/or initiating the apoptosis

contributes to the loss of control of cell proliferation and differentiation

pathway.

and the acquisition of capabilities, such as tissue invasion, the ability

o

to metastasize, and angiogenesis

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

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 the first phase, G1 , preparations are made to replicate the genetic material

>

S phase for DNA synthesis »

The main brake on the process is the

, Rb

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 »

most cancers have mutations that

, including Nearly every cancer has one or more genetic lesions in the  that permits progression to S phase.

.

.

o

This mutation is underscored by the neoplastic transformation

o

This virus has two main oncogenes , E6 and E7. E6 acts to

If the cell determines that it is unready  to move ahead with DNA replication, a number of inhibitors are

»

!

mechanism of human papillomavirus.

increase the rapid turnover of p53, and E7 acts to inhibit Rb function; inhibition of these two targets is required for transformation of epithelial cells.

5

SIGNAL TRANSDUCTION PATHWAYS IN CANCER CELLS

-

chemical changes can result from signal transduction pathways, but  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

  (Fas-associated death   to death domain motifs of the

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.

  of apoptosis is initiated by the release of 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.

-

CANCER AS AN ORGAN THAT IGNORES ITS NICHE

-

-

the mitochondrial outer membrane via their carboxyl termini

fundamental cellular defects that create a malignant neoplasm act at !

the cellular level

#

9

—such a mass consists of about 10  cells. lethal tumor burden is about 10  to 10  cells.

-

human tumors grow by

can serve as a homeostatic mechanism to promote survival for the cell by recycling cellular components to provide

13

-

necessary energy

—this means that not #

every daughter cell produced by a cell division is itself capable of

appears to play conflicting roles in the development and survival of cancer

dividing. o

growth fraction of a tumor

o

growth fraction of the first malignant cell is 100%, and by the time

.

!

Necrosis - digestion of cellular components and rupturing of the cell

membrane METASTASIS

a patient presents for medical care, the growth fraction is 2–3%

o

Autophagy - degradation of proteins and organelles by lysosomal

proteases

cancers usually become clinically detectable when a primary mass is at 12

Antiapoptotic members (e.g., Bcl-2, Bcl-XL, and Mcl-1) associate with

or less

-

Accounts for the vast majority of deaths  from solid tumors

a tumor is slowing its own growth over time

-

three major features of tissue invasion are

!

epithelial-mesenchymal transition (EMT)- process by which cells lose

#

Some cells are hypoxemic and have inadequate supply of

#

Some have sustained too much genetic damage to complete

nutrients and energy . their epithelial properties and gain mesenchymal properties

the cell cycle   but have lost the capacity to undergo apoptosis and therefore survive but do not proliferate

-

Malignant cells that metastasize  but retain the capacity for unregulated proliferation.

6

-

-

Malignant cells that gain access to the circulation must then repeat

o

those steps at a remote site, find a hospitable niche in a foreign tissue,

dynamic balance of pro- and antiangiogenic factors is tipped in

avoid detection by host defenses, and induce the growth of new blood

favor of vessel formation by the effects of the tumor on its

vessels.

immediate environment.

The rate-limiting step for metastasis is the ability for tumor cells to

o

Stimuli for tumor angiogenesis include hypoxemia, inflammation,

survive and expand in the novel microenvironment of the metastatic

and genetic lesions in oncogenes or tumor suppressors that alter

site, and multiple host-tumor interactions determine the ultimate

tumor cell gene expression.

outcome

CANCER METABOLISM

-

The angiogenic switch is a phase in tumor development when the

One of the distinguishing characteristics of cancer cells is that they

Tumor vessels: #

Are not normal; they have chaotic architecture and blood flow

#

Are tortuous, dilated with an uneven diameter, excessive

have altered metabolism as compared with normal cells in supporting

branching and shunting #

survival and their high rates of proliferation. -

Many cancer cells use aerobic glycolysis (Warburg effect) to metabolize

acidosis #

glucose, leading to increased lactic acid production -

Tumor blood flow is also variable with areas of hypoxemia and

Vessel

A number of proteins in cancer cells, including CMYC, HIF1, RAS, p53, #

openings,

widened

cells.

The inefficient utilization of glucose also leads to a need for alternative

MECHANISMS OF TUMOR VESSEL FORMATION

-

glutamine. o

numerous

Lack perivascular cells such as pericytes and mooth muscle

controlling the Warburg effect. metabolic pathways for other compounds as well, one of which is

have

interendothelial junctions

pRB, and AKT, are all involved in modulating glycolytic processes and -

walls

most tumor blood vessels arise by the process of

, in which

tumors secrete trophic angiogenic molecules, the most potent being

Glutamine is also inefficiently used by cancer cells.

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

 may be more dependent on VEGFR signaling for growth 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.

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 thus, a critical aspect in the growth of tumors is the development of new blood vessels, or angiogenesis.

-

Angiogenic switch: the ability of the tumor to promote the formation

of new capillaries from pre- existing host vessels.

7