Cancer Cancer Is an umbrella term covering a range of conditions characterized by unscheduled and...

CancerCancer

Cancer Is an umbrella term covering a range of conditions characterized by unscheduled and uncontrolled cellular proliferation.

11Molecular Biology of Molecular Biology of CancerCancer

Topics to be covered in the courseTopics to be covered in the course

The hallmarks of cancer (Introduction to the biology of cancer) Cell Proliferation, Differentiation and cell death

Control of cellular proliferation (cell cycle) Control of Apoptosis External control of cell cycle (Signal Transduction)

Molecular carcinogenesis Cellular transformation Oncogenes Tumor-Suppressor Genes Recurring Chromosome Rearrangements and Cancer-Associated Gene Mutations in

Human Cancer

Molecular mechanisms involved in carcinogenesis Alterations of Signaling to Cell Division and Survival in Cancer. Mechanisms of Regulation of Cancer-Related Genes

Invasion and Metastases Tumor Angiogenesis

Molecular Biology of CancerMolecular Biology of Cancer22

ReferencesReferences

Holland-Frei Cancer Medicine 6th edition (April 2003): By Donald W., Md Kufe, Raphael E., Md Pollock, Ralph

R., Md Weichselbaum, Robert C., Jr., Md Bast, Ted S., MD Gansler By BC Decker

Molecular Mechanisms of Cancer (2007) By Georg F. Weber

Introduction to the Cellular and Molecular Biology of Cancer (2005) By Margaret A. Knowles and Peter J. Selby


Exams and homeworkExams and homework

Midterm exam (30 degrees) Final Exam (30 degrees) Assay (10 degrees) Homework (10 degrees)

44 Molecular Biology of CancerMolecular Biology of Cancer

The hallmarks of cancerThe hallmarks of cancer

55Molecular Biology of Molecular Biology of CancerCancer

OverviewOverview

With few exceptions, cancers are derived from single somatic cells and their progeny.

The emerging neoplastic cells accumulate a series of genetic or epigenetic changes that lead to changes in gene activity, and thus to altered phenotypes.

Ultimately, a cell population evolves that can disregard the normal controls of proliferation and territory and become a cancer.


Six hallmark features of the cancer Six hallmark features of the cancer cell phenotypecell phenotype

1. disregard of signals to stop proliferating

2. disregard of signals to differentiate

3. capacity for sustained proliferation

4. evasion of apoptosis

5. Invasion

6. angiogenesis


Tumors arise from normal tissuesTumors arise from normal tissues

Tumor is not a foreign mass invading the body from outside world


continuity between normal and cancerous tissue in the small intestine

Four major types of new tissue growthFour major types of new tissue growth99 Molecular Biology of CancerMolecular Biology of Cancer

In normal skin, each cell division gives rise to one cell that retains the capacity to divide and one that differentiates.

Comparison of normal and neoplastic Comparison of normal and neoplastic growth in the epithelium of the skingrowth in the epithelium of the skin


The uncontrolled cells of a cancer can grow as: A solid mass, which is called a tumor. Unconnected and free-floating, as in a cancer of blood

cells, e.g., leukemia The term neoplasm, meaning “new growth”, is used

to refer to many kinds of cancer to signify an abnormal growth.


Tumors are of two basic typesTumors are of two basic types

1. Benign: A tumor mass contained, e.g. by a capsule of connective

tissue not able to spread

2. Malignant: Tumor cells that escape from their site of origin and

move off to grow elsewhere The distant sites of growth are called “metastases.”


A Malignant Tumor vs a Benign A Malignant Tumor vs a Benign TumorTumor

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 and 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 tumor 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.

Once they reach a clinically detectable stage, malignant tumors generally show evidence of significant growth, with involvement of surrounding tissue, 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 cachexia (extreme body wasting), hemorrhage, and infection.


usually

Comparison of benign and malignant Comparison of benign and malignant growthsgrowths

_____________________________________________

Feature Benign Malignant

_____________________________________________

Metastasis no yes

Invasionno yes

Edges encapsulatedirregular

Growth rate low high

Nuclei & nucleoli normal variable, irregular

Life-threatening uncommon usual

_____________________________________________


Epithelium-derive neoplasmsEpithelium-derive neoplasms

The most common types of human cancers The neoplasms which are derived from

epithelium are called “carcinomas”. These tumors are responsible for more than

80% of the cancer-related deaths. Most of the carcinomas fall into two major

categories: Squamous cell carcinomas: arising from stratified

squamous epithelium Adenocarcinomas: arising from glandular

epithelium.


Nonepithelial cancersNonepithelial cancers

Sarcomas: Derive from a variety of mesenchymal cell types:

fibroblasts (connective tissues), adipocytes (fat), osteoblasts (bone), myocytes (muscle)

constituting ~1% of the tumors in the oncology clinic.



Cancers arise from various cell types of blood-forming tissues:

lymphoma – solid tumors of lymphocytes, most frequently found in lymph nodes

leukemia – tumors of “white cells” of the blood, usually moving freely through the circulation



Tumors arising from cells of the central and peripheral nervous system:

Glioblastoma tumors of astrocytes


“oma” usually indicates a tumor. carcinoma, sarcoma, lymphoma, myeloma,

neuroblastoma, etc. Rarely, the “oma” describes a nonneoplastic

conditions. granuloma, is a mass of granulation tissue resulting

from chronic inflammation or abscess.


Classification of Human Tumors by Classification of Human Tumors by Tissue TypeTissue Type

Tissue of Origin Benign Malignant

EpitheliumSurface epitheliumGlandular epithelium

PapillomaAdenoma

CarcinomaAdenocarcinoma

Connective tissueFibrous tissueBone

Fibroma Osteoma

Fibrosarcoma Osteosarcoma

Endothelial tissueBlood vesselsLymph vessels

Hemangioma Lymphangioma

Hemangiosarcoma Lymphangiosarcoma

Neural tissue & its derivativesGlial tissueMeninges Nerve sheath MelanocytesRetina

Glioma MeningiomaNeurofibromaPigmented nevus-

Glioblastoma multiformeMeningeal sarcomaNeurofibrosarcomaMalignant melanomaRetinoblastoma


Cell Proliferation and DifferentiationCell Proliferation and Differentiation

The biology of cell division, differentiation, and apoptosis is exceedingly similar in both normal and cancer cells.

The cancer cell differs from its normal counterpart in that it is aberrantly regulated.

Cancer cells like normal cells generally contain the full complement of biomolecules necessary for:

survival, proliferation, differentiation, cell death, and expression of many cell type-specific functions.

Failure to regulate these functions properly, however, results in an altered phenotype and cancer.


Four cellular functions tend to be Four cellular functions tend to be inappropriately regulated in a neoplasminappropriately regulated in a neoplasm

1. The normal constraints on cellular proliferation are ineffective.

2. The differentiation program can be distorted: The tumor cells may be blocked at a particular stage of

differentiation. They may differentiate into an inappropriate or abnormal

cell type.3. Chromosomal and genetic organization may be

destabilized: variant cells arise with high frequency. Some variants may have increased motility or enzyme

production that permits invasion and metastases.4. The tightly regulated cell death program (apoptosis) may be

dysregulated.


PROLIFERATION PROLIFERATION

Molecular Biology of Molecular Biology of CancerCancer 2626

One hallmark of cancer is that most One hallmark of cancer is that most are genetically clonal, are genetically clonal,

Cancers usually arise by expansion of a single cell.

Evidence from X-inactivation Red and blue colors indicate cells with

one or the other X chromosome inactivated.

Note that all the cancerous cells that form the “tumor mass” in the middle of the tissue show only one kind of X-inactivation, suggesting that they all grew as a clone from a single cell.


Cancer evolves through continual genetic Cancer evolves through continual genetic evolution of mutant cells by a process of natural evolution of mutant cells by a process of natural selection.selection.

In cancers in which preneoplastic lesions can be identified, the preneoplastic cells are likely to be genetically distinct from the overtly neoplastic cells.

Genetically abnormal cells are generated as a result of environmental insult or normal errors in replication.

Some small fraction of these cells escapes normal controls on cell proliferation and increases their number.

As this pool of mutant cells proliferates, additional mutant variants are continuously generated. If the result of these additional mutations provides a selective growth advantage, then the mutant variant will increase its relative number.

Through multiple rounds of proliferation, mutation, and selection a neoplastic variant evolves to cause cancer.


Two parameters will critically affect the rate Two parameters will critically affect the rate of this clonal evolutionof this clonal evolution

The mutation rate, and the rate of proliferation. The rate of neoplastic transformation will increase

with mutations that increase the rates of proliferation or mutation rate.

Such mutations are more likely to be detected in cancer cells than other types of mutations.

If such a mutation is inherited, the incidence of cancer within such a family is expected to be significantly higher than normal.


The accumulation of multiple mutations in a The accumulation of multiple mutations in a single somatic cell is very improbablesingle somatic cell is very improbable

The probability of mutation is low (one in about 100 million/base pair/cell division)

To get mutations that alter genes that control cellular behavior is VERY unlikely

To get mutations in many different genes that control cell behavior is VERY VERY unlikely!

The road to cancer therefore seems to involve the introduction of abnormal instability into the genome of the cell that is becoming cancerous


A “successful” cancer is one that acquires just the right degree of genetic instability, allowing it to mutate at rates that give it selective advantages but not so fast that it dies


Cancer Cancer Is an umbrella term covering a range of conditions characterized by unscheduled and...

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