molecular basis of cancer progression1

8/14/2019 Molecular Basis of Cancer Progression1

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Molecular Basis and TherapeuticApproaches of Cancer

Objective:

To understand to the process oftumor progression, angiogenesis,metastasis and its implication for

cancer therapy

Ratchada Cressey, Ph.D


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Some Important Facts:

General US- 500,000 deaths per years

2nd only to heart disease as causes of

motality 1 in 3 in developing country

50% die/survive 17% cured by chemotherapy

1 million new cases per year Lung, large intestine, breast and prostate

cancer = 55% of new cases and deaths in the US


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2nd only to accident as cause of motality

Distribution of the types of cancer

according to the area Bangkok (lung cancer) North-East (liver cancer) North (lung cancer) South (cancer of GI tract, lung cancer)

Some Important Fact: Thailand


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Why do people of cancer die?

Local EffectsParaneoplastic Syndromes

Cancer cachexia


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I. Local effects Tumor Impingement on nearby structures

Pituitary adenoma on normal gland, Pancreatic

carcinoma on bile duct, Esophageal carcinoma on lumen Ulceration/bleeding

Colon, Gastric

Infection (often due to obstruction)

Pulmonary infections due to blocked bronchi (lungcarcinoma), Urinary infections due to blocked ureters(cervical carcinoma)

Rupture or Infarction Ovarian


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II.Paraneoplastic Syndromes

Peptide Product Condition

PTHrP or PTH hypercalcemia

insulin/insulin-like hypoglycemia

gastrin Zollinger-Ellison dis.

erythropoietin polycythemia

ACTH Cushings disease


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unique form of protein-calorie malnutrition affects 50 to 80% of human cancer patients

common cause of death symptoms

weakness, fatigue, anorexia physical examination abnormalities

weight loss, skeletal muscle atrophy, adipose tissue loss,myopathy

clinical pathology abnormalities anemia, decreased serum albumin, glucose intolerance,

energy

III.Cancer Cachexia


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Multi-step ofcarcinogenesis


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The cell cycle is regulated by a number ofsignaling systems


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Tumors require the continuing

formation of new blood vessels:

Supply oxygen and nutrients

Supply endocrine and paracrinegrowth-enabling factors


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Growth of tumor is dependent on

angiogenesis


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What is angiogenesis?

Angiogenesis is fundamental tohealing, reproduction, embryonicdevelopment.

During development, new bloodvessels originate from endothelialcell precursors (angioblasts) by aprocess called VASCULOGENESISor from pre-existing blood vessels

by ANGIOGENESIS.

Both processes are mediated bygrowth factors.


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Angiogenesis: Hypoxia

Carmeliet & Jain, 2000 Nature

Tumor cells locatedmore than 100 m(diffusion limit foroxygen) away fromblood vessels becomehypoxic.

Clones are selected inhypoxic tumors thatswitch toproangiogenic

phenotype. Hypoxia inducible

factors (HIFs)increase transcriptionof angiogenic genes.


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The angiogenesis process begins with the degradation of the

basement membrane by proteases secreted by activatedendothelial cells that will migrate and proliferate, leading to theformation of solid endothelial cell sprouts into the stromal space.

Then, vascular loops are formed and capillary tubes develop withformation of tight junctions and deposition of new basement

membrane.


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The actual process of angiogenesisinvolves a number of steps including:

The release of proteases from "activated endothelialcells"

The degradation of the basement membrane surrounding

the existing vessel The migration of the endothelial cells into the interstitial

space

Endothelial cell proliferation

The formation of the lumen

The generation of new basement membrane with therecruitment of pericytes

Fusion of the newly formed vessels

And resuming blood flow


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I. Breaking down of the

basement membrane In order to create new capillaries, endothelial

cells of existing blood vessels must degrade the

basement membrane. This process of endothelial cell invasion requires

the help of

Urokinase-plasminogen activator (uPA)

Matrix metalloproteinases (MMPs).


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Plasmin degrades several extraceullar matrix (ECM)

components such as fibrin, fibronectin, laminin, and the

protein core of proteoglycans. Plasmin can also activateserveral MMPs such as MMP-1, MMP-3, and MMP-5.

Most types of ECM contain collagens, elastin, various

glycoproteins (such as fibronectin, laminin, entactin, and

nidogen), proteoglycans, and glycosaminoglycans.

There are at least 16 different members of MMPs that break

down different components of the ECM.

I. Breaking down of the

basement membrane (2)


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II. Endothelial cells migration

and proliferation After the degradation of the ECM, "leader"

endothelial cells migrate through the broken

down matrix Proliferating endothelial cells migrate into

the degraded matrix. Then they arestimulated by growth factors that were

released from the degraded matrix.


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III. Cell and Matrix Interactions

The final phase of angiogenesis includesthe construction of capillary loops and

the determination of the polarity of theendothelial cells.

These are required for lumen formation andinvolve cell-cell contact and cell-ECMinteraction.


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Alterations in at least fourendothelial cell functions occur

during angiogenesis

(1) an increase in proliferation, which provides newcells for the growing and elongating vessel, with asubsequent return to the quiescent state once thenew vessel is formed

(2) an initial increase and subsequent decrease inlocomotion (migration), which allows the cells to

translocate toward the angiogenic stimulus and to

stop once they reach their destination(3) endothelial cell-to-cell interactions

(4) interactions with the extracellular matrix.


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Angiogenic factors Cytokines, chemokines and angiogenic

enzymes are direct-acting molecules that

activate a broad range of target cells VEGF family and angiopoietins which act on

endothelial cells specifically

Indirect-acting factors whose effect results

from direct-acting factors frommacrophages, endothelial cells, or tumorcells.


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2. VEGF

(Vascular endothelial growth factor)

Expression of VEGF is required during

embryonic development for theformation of normal blood vessels,

Loss of even a single VEGF allele islethal, suggesting that normal VEGF

levels are critical for the regulation ofvessel development.


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VEGF has been studied both in vivo and in vitroand both have given similar results:

In vivo - VEGF has been shown to regulatevascular permeability. This is important

because it is one of the initiation steps ofangiogenesis.

In vitro - VEGF has been shown to stimulateECM breakdown, migration, proliferation and

with other enzymes.


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VEGF mediates angiogenesis throughits tyrosine kinase receptor


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VEGF and Oxygen

VEGF levels are regulated by tissue oxygentension

Exposure to hypoxia induces VEGF expressionrapidly and reversibly, through both increasedtranscription and stabilization of the mRNA.

Hypoxic upregulation of VEGF thus provides acompensatory mechanism by which tissues (or

tumors) can increase their oxygenation throughinduction of blood vessel growth.

Hypoxia also regulates the VEGF receptorgene expression


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Under conditions ofhypoxia, ECs up-regulate VEGF, which,

once secreted, maythen interact with itsreceptor. Such anautocrine loop providesthe basis foramplification of any

given VEGF secreted oradministered into anischemic territory. ECsstimulated to proliferatein response to VEGFmay then serve as

additional sources ofVEGF synthesis, thusamplifying the effect ofthe initial dose of VEGF.


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Factors secreted by hypoxic myocytes up-regulate VEGFreceptor expression on ECs within the hypoxic milieu. Suchlocalized receptor expression may explain the finding thatangiogenesis does not occur indiscriminately, but rather at sitesof tissue ischemia. (From Horowitz et al)


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Survival: Correlation With BloodVessel Number and VEGF Levels

Takahashi et al.Arch Surg. 1997;132:541.


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Role of Angiogenesis in Primary andMetastatic Tumors


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Metastasis: Correlation With BloodVessel Number and VEGF Levels

Takahashi et al. Cancer Res. 1995;55:3964.


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ANTIANGIOGENICTHERAPY

~ 200 biotech and bigpharma companies arepursuing angiogenesis

research


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Anti-VEGF drugs


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Anti-VEGF drug


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Inhibit Tumor Angiogenesis

Fidler et al. In DeVita et al. Cancer: Principles and Practice of Oncology. 6th ed. 2001:137.


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Angiogenesis Inhibitors Phase III Clinical Trials

Product Description Disease Target

Avastatin

(Genentech)

Monoclonal antibody thatdisables vascular endothelialgrowth factor (VEGF), a

promoter of angiogeneis

Breast and colorectalcancer

BMS275291

(Bristol-Myers Squibb)

Synthetic compound havingmultiple effects

Non-small cell lungcancer

Interferon Protein that inhibits releaseof growth factors such asVEGF

Various tumors

Jain & Carmeleit, Scientific American (December, 2001) 39-45


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Angiogenesis InhibitorsPhase III Clinical Trials

Product Description Disease Target

Marimastat

(British Biotech)

Synthetic compound havingmultiple effects

Breast and prostate cancer

Neovastat(Aeterna)

Naturally occurring inhibitorwith a range of properties

Non-small cell lungcancer and renal cancer

SU5416

(Sugen)

Synthetic compound thatblocks the receptor for

VEGF

Colorectal cancer

Thalidomide

(Celgene)

Organic molecule whosespecific mode of action isunknown

Renal cancer and multiplemyeloma

Jain & Carmeleit, Scientific American (December, 2001) 39-45


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Angiogenesis Inhibition

Difficult to completely inhibit angiogenesis Range of factors inducing angiogenesis

Difficulty in eliminating all activity for particularfactor

Angiogenesis is required for normalprocesses possible side effects

Suppress growth of metastases incombination with other treatments


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Paradox: antiangiogenic therapyincreases effectiveness ofconventional therapies Would expect that reduced blood

supply to tumor would make

chemotherapy less effective


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For some antiangiogenic therapies,delivery of chemotherapeutic agents,

nutrients and oxygen improves Antiangiogenic factors normalize tumor

vasculatureTumor blood vessels structurally disorganized,

dilated, leakyAngiogenesis inhibitors can reduce diameter,

make vessels less leaky


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molecular basis of cancer progression1

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