Islamic University of Gaza Faculty of...

Islamic University of GazaFaculty of Medicine

• A critical balance is maintained between cell growth, proliferation, differentiation, and apoptosis.

• This critical balance is disrupted in presence of tumor inducing agents:– Inherited genetic defect– chemical carcinogen– viral infection– Irradiation

• Out of control cellular growth neoplasia

Molecular Biology, 2011‐20122

1. Immortalization:– The ability to grow and divide indefinitely.

2. Transformation:– Failure to observe normal constraints of growth; i.e. growth occurs independently of cell growth factors.

– Possible formation a sold tumor.3. Angiogenesis – the growth of new blood vessels4. Metastasis:

– Migration from the tissue of origin to other parts of the body where they begin to colonize.


• Benign:– A tumor mass contained, e.g. by a capsule of connective tissue

– not able to spread• Malignant:

– Tumor cells that escape from their site of origin and move off to grow elsewhere

– The distant sites of growth are called “metastases.”


1. Malignant tumors invade and destroy adjacent normal tissues. Benign tumors grow by expansion, are usually encapsulated, and do not invade surrounding tissue.– Benign tumors may, however, push aside normal tissue

– become life‐threatening if they press on nerves or blood vessels.


2. Malignant tumors metastasize through lymphatic channels or blood vessels to lymph nodes and other tissues in the body. Benign tumors remain localized and do not metastasize.– Primary tumor – tumor growing at the anatomical site where tumor progression began and proceeded to yield this mass

– Metastatic tumor – tumor forming at one site in the body, the cells of which are derive from a tumor located elsewhere in the body


3. Malignant cells tend to be anaplastic (less differentiated) than normal cells of origin. Benign tumors usually resemble normal tissue more closely than malignant tumors do.– Anaplasia: reversion to a less differentiated structure

4. Malignant tumors usually, but not always, grow more rapidly than benign tumors.– Malignant tumors generally reach a clinically detectable stage over weeks or months

– benign tumors often grow slowly over several years.


5. Malignant neoplasms continue to grow even in the face of starvation of the host– They press on and invade surrounding tissues, often interrupting vital functions.

– The most common effects on the patient are extreme body wasting, hemorrhage, and infection.


• Cancer is a group of genetically diverse disorders– Each individual tumor can have its own “genetic signature”

• The mutations acquired by a tumor cell become a heritabletrait of all cells of subsequent generations

• Cancer is a multistep disease.– Requires the accumulation of estimated 4‐8 genetic changes over the course of years.


• Gene mutations that increase the risk for developing cancer can be inherited or acquired


• Result from spontaneous or environmentally inflicted errors during DNA replication.1. Those that result from a gain of function

• Inappropriate activation of oncogenes (normally stimulatory for growth)

2. Those that result from a loss of function• Inactivation of tumor suppressor genes (normally inhibit cell growth)


• Oncogenes are genes whose products have the ability to cause malignant transformation of eukaryotic cells.– They were originally identified as the “transforming genes” carried by some DNA and RNA tumor viruses

– Referred to by a three letter‐code (e.g. src, myc), reflecting the virus from which they were first isolated.

– Some viruses carry more than one oncogene (e.g. erbA, erbB)


• An oncogene is a mutant allele of a proto‐oncogene

• Proto‐oncogene:– A class of normal cellular genes that normally encode growth promoting and survival proteins

– The normal counterparts in the eukaryotic genome to the viral oncogenes

• with the potential to give rise to oncogenes– Designation “c‐” indicates their cellular origin– Designation “v‐” signifies original identification in retroviruses


• Different types of alterations are responsible for activation of a proto‐oncogene– Gene amplification– Point mutations– Promoter mutations– Ectopic and heterochronicmutations of proto‐oncogens

– Chromosomal translocations• Cause misexpression of genes• Or create chimeric genes encoding proteins with novel functional properties



Either type of changes is dominant over its allelic proto‐oncogene.

• Based on normal function and sequence homology to other known proteins– Involved in all levels of various signal transduction cascades that control cell growth and proliferation, differentiation, and apoptosis.

• Secreted growth factors• Cytoplasmic proteins such as serine kinases and tyrosine kinases

• Surface and membrane‐associated proteins involved in signal transduction

• Transcription factors

• Deregulated and overexpressed in human cancers


• The human c‐src gene encodes a membrane‐associated non‐receptor tyrosine kinase– Normally inactivated by c‐Src tyrosine kinase (CSK)

• Phosphorylates a tyrosine in c‐Src C‐terminal domain– Normally activated by C‐terminus dephosphorylationby phosphatases

• Active c‐Src phosphorylates target proteins on specific tyrosines– Activation of signal‐transduction pathways having a critical role in cell growth differentiation and death


• v‐Src differs from c‐Src by substitution of sequences at the C‐terminus.– v‐Src thus remains in the “open” or active conformation


• Overexpression of c‐Src and an increase in its enzymatic activity has been observed in numerous cancer types– Including colorectal, hepatocellular, pancreatic, gastric, esophageal, breast, ovarian, and lung cancers.

• Primary role of c‐Src in cancer progression and metastasis include deregulated :– cellular proliferation– cell adhesion– Invasion– Motility


• Mutations in tumor‐suppressor genes (TSGs) contribute to malignancy through loss of function of both alleles of the gene.

• TSGs are highly heterogeneous– Gatekeeper TSGs encode:

• Regulators of various cell‐cycle checkpoints• Mediators of programmed cell death

– Caretaker TSGs encode:• Proteins responsible for detecting and repairing mutations• Proteins involved in normal chromosome disjunction during mitosis

• Components of programmed cell death machinary


• The two hits hypothesis:–Cancer arises when there are 2 independent mutations or “hits” that lead to loss of function of both tumor suppressor alleles at a locus.

– Loss can be either sporadic or heritable.


• One option involves:– First hit: loss of one allele is inherited through the germline• an individual is said to have a “genetic predisposition” to cancer.

– Second hit: Sporadic mutation of the second allele in a somatic cell leads to tumorigenesis.

• Another option involves:– Loss of function of a tumor suppressor gene occur at a much lower frequency by two sporadic mutations (hits) in the same cell.


• Has been implicated in the regulation of DNA replication, cell differentiation, DNA repair, cell cycle checkpoints, and apoptosis.

• One of the normal cellular functions of pRB is to prevent cells from entering S phase, the phase in which DNA is replicated


• In acute lymphoblastic leukemia (ALL)– CDK2 catalytic activity high pRB is kept phosphorylated effectively “absent”

– ALL have lost their ability to differentiate or undergo apoptosis, causing an accumulation of malignant cells.


• It regulates multiple components of the DNA damage control system

• One of the genes most commonly induced in response to cellular stress signals.

• As a transcription factor, p53 can activate or repress many target genes.– Over 100 genes regulated by p53 have been identified


• Alterations in the p53 gene have been linked to many cancers– including cervix, breast, bladder, prostate, liver, lung, skin, and colon.

• 80% of all human cancers show either – deletion of both p53 alleles absence of p53 protein – or a missense point mutation in one allele.

• Mutations in p53 are Li–Fraumeni syndrome– Hereditary cancer syndrome– predisposes patients to brain tumors sarcomas, leukemia, and breast


• A missense point mutation in one allele of p53 a dominant negative mutant protein.– lost tumor suppressor function – Also inhibits wild‐type p53 activity by heterotetramerization


• Many cancers are associated with alterations in chromosomes, particularly translocations

• Many breakpoints in tumor cells are very close to a known proto‐oncogene– bring a cellular protooncogene under the control of the wrong promoter and/or enhancer


• A single event triggers chronic myelogenous leukemia (CML):– a chromosomal translocation fuses the genes encoding ABL and BCR

• BCR is a GTPase‐activating protein essential for activation of the ABL tyrosine kinase.– c‐abl is the cellular homolog of v‐abl(Abelson murine leukemia viral oncogene homolog 1).

– The resulting fusion protein BCR‐ABL has unregulated tyrosine kinase activity


• A small organic molecule called imatinib mesylate (Gleevac)– inhibits BCR‐ABL activity in early‐stage patien

– controls chronic myelogenous leukemia

• When imantinib occupies the kinase pocket, the action of BCR‐ABL is inhibited, preventing phosphorylation of its substrate.


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