BIOLOGY OF TUMOR GROWTHDepartment of PathologyGadjah Mada University School of Medicine

BIOLOGY OF TUMOR GROWTHThe tumor cells tend to replicate rather than to differentiate due to genetic alterations (oncogene activation, anti-oncogene suppression/tumour suppressor gene, etc)Most tumors are of monoclonal originIncreasing in the proportion of stem cells undergoing replication, and a corresponding decrease in the proportion progressing to full end-stage maturation3 factors influencing are: growth fraction, angiogenesis, and doubling time

The biology of tumor Normal cells

Malignant cells

Changes:GenotypicPhenotypic

BIOLOGY OF TUMOR GROWTHThe tumor cells tend to replicate rather than to differentiate due to genetic alterations (oncogene activation, anti-oncogene suppression, etc)Most tumors are of monoclonal origin

BIOLOGY OF TUMOR GROWTH Most malignant tumors normally passing four phases : Transformation Growth of transformed cells Local invasion Distant metastases

BIOLOGY OF TUMOR GROWTHMultiple factors that influence tumor growthKinetics of tumor growthTumor angiogenesisTumor progression and heterogeneity

BIOLOGY OF TUMOR GROWTHKinetics of tumor growthHow long does it take to produce a clinically overt tumor mass ?This depends on three variables:The doubling time of tumor cellsGrowth fractionCell production and loss

Kinetics of tumor growthThe doubling time of tumor cellsOriginal transformed cell (+ 10u in diameter) must undergo at least 30 population doublings to produce 109 cells (weighing + 1gm) ---- the smallest clinically detectable mass. In contrast, only 10 further doubling cycles are required to produce a tumor containing 1012 cells (weighing + 1 kg), which is usually the maximal size compatible with life.

The doubling time of tumor cells

Kinetics of tumor growthThe doubling time of tumor cellsIs the amount of time a tumor to double in cell numbersDoubling time for malignant tumor is not necessarily longer than normal cell origin. Benign tumors grow more slowlyOne factor in doubling time is the number cells in the growth phaseAnother factor, is the number of cells that die and never replicated, that is, most cells in a tumor, much more than 90%

Kinetics of tumor growthThe doubling time of tumor cellsCharacteristics of tumor cells:Cells in the growth phase are the most susceptible to chemotherapeutic agentsType of tumor vary in their doubling time, and the same type of tumor varies from patient to patient

Kinetics of tumor growthThe doubling time of tumor cells A lesson to be learnt from the concept of doubling time / tumor growth is :By the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle, orWhen tumors are finally discovered, they have been around for a long time, growing unnoticed because of their small size, orBy the time the tumor achieves a clinically noticeable size, its rate of growth will become more clinically noticeable

Kinetics of tumor growthGrowth FractionThe proportion of tumor cells within the tumor cell population that are in replicative poolTumor continue to grow cells leave the replicative pool, owing to:- shedding or lack of nutrient- by differentiating- reversion to G0Most cells within cancer remain in the G0 phaseIn some rapidly growing tumors, the growth fraction is approximately 20%

Kinetics of tumor growthGrowth fraction

CANCER STEM CELLS & CANCER LINEAGEA clinically detectable tumor contain hetero-geneous population of cells, which originated from the clonal growth of a single cells difficult to identify the cancer stem cellsCancer stem cells (T-IC: tumor-initiating cells) were recently identified in breast tumors (< 2% of cells) and aml (< 0.1 1%)Whether such cencer stem cells exist in all tumors is not yet clear.

CANCER STEM CELLS & CANCER LINEAGETo maintain their self-renewing capacity, leukemic T-IC require the BMI1 gene which repress the cell-cycle inhibitors p161NK4a and p14ARFStrong experimental support idea: cancer stem cells of leukemia are the initial target for transformation important implication for cancer treatment aimed at the elimination of proliferating cells

CANCER STEM CELLS & CANCER LINEAGECancer stem cells similar to their normal counterpart have a low rate of replication cancer therapies that may efficiently kill the replicating progeny of the cancer stem cells would leave in place the cells capable of generating the tumors tumor can easily recur after treatment.

Telomerase activities and maintenance of telomere length are essential for the maintenance of replicative potential in cancer cells

The important clinical implication of tumor cell kineticsCancer chemotherapyMost antineoplastic agents are mostly effective on cycling cells high growth fraction tumors are very sensitive to anti-cancer drugsDebulking the left cells tend to re-enter the cell cycle sensitiveLatent period of tumorsMost tumor cells leave replicative pool latent period (months/years before a tumor becomes clinically detectable)

Kinetics of tumor growthCell production and lossProgressive growth of tumors and the rate of growth is determined by how much cell production exceeds cell loss

In tumors with relatively high growth fraction, the imbalance is large more rapid growth

BIOLOGY OF TUMOR GROWTHTumor angiogenesisBlood supply :Tumor cannot enlarge beyond 2 mm in diameter or thickness unless they are vascularized. Presumably the 2 mm zone represent the maximal distance across which oxygen and nutrients can diffuse from blood vessels.

BIOLOGY OF TUMOR GROWTH Tumor angiogenesisAngiogenesis is not only for tumor growth, but also for metastasizeAngiogenesis is a necessity for biological correlation of malignancy. Several studies have revealed a correlation between the extent of angiogenesis (microvessel density) and the probable of metastases in melanomas and cancer of the breast,lung,colon and prostate

BIOLOGY OF TUMOR GROWTH Tumor angiogenesisEffect of neovascularizationPerfusion of supply nutrients, oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting polypeptides such as IGF, PDGF, GM-CSF, and IL-1

BIOLOGY OF TUMOR GROWTH Tumor angiogenesisHow do growing tumors develop blood supply Tumor contain factor that are capable of affecting the entire series of events involved in the formation of new capillaries Tumor Associated Angiogenic Factors (TAAF) may be produced by tumor cells or inflammatory cells (macrophage) that infiltrate tumors.TAAF : many, but two most important : VEGF and bFGF --- expressed in wide variety of tumor elevated levels can be detected in the serum and urine

BIOLOGY OF TUMOR GROWTH Tumor angiogenesisAntiangiogenesisTumor cells also induced and produced antiangio-genesis molecules.Tumor growth is controlled by the balance between angiogenic factors and antiangiogenic factor (inhibit angiogenesis).Example of Antiangiogenesis :Induced: Thrombospondin1Produced: Angiostatin, endostatin, tumstatin

BIOLOGY OF TUMOR GROWTH : Tumor AngiogenesisDysorganized vessels within the tumor mass

Tumor angiogenesis compared to normal blood vesselThe tumor vasculature is formed from circulating endothelial precursor cells and existing host vessel. Myofibroblasts give rise to pericytes at the periphery of the vessels. The tumor vessels are unstable and leaky.

Tumor angiogenesis compared to normal blood vesselArterioles, capillaries, and veins are disorganized and unidentifiable.

AngiogenesisBecause angiogenesis is critical for the growth and spread of tumors, much attention is focused on the use of angiogenesis inhibitors therapy Success has been achieved in treating fairly large tumors in mice by adm. of endostatin and tumstatin (anim.exp.)

Biologi penyebaran tumorTahap invasi1. Lepasnya ikatan sel tumor satu sama lain2. Sel tumor melekat pada komponen matriks ekstraselular3. Degradasi matriks ekstraselular4. Migrasi sel tumor menembus jaringan interstisial/matriks ekstraselularTahap metastasis1. Invasi ke dalam pembuluh darah (intravasasi)2. Tertahan di dalam vasa darah/limfe, dan bertahan hidup3. Ekstravasasi4. Bertahan hidup, angiogenesis, dan tumbuh sebagai metastasis

BIOLOGY OF TUMOR GROWTH Tumor progression and heterogeneityOver period of time the tumor become more aggressive and acquire greater malignant potential tumor progressionMost malignant tumor are monoclonal in origin but by the time they become clinically evedent, their constituent cells are extremely heterogenous

Malignant potentialAcclerated growth, invasiveness, ability to form distant metastasisInvasion and metastasis are biologic hallmark of malignancyFour steps of invasionDetachment of tumor cellsAttachment of tumor cells to matrix componentsDegradation of ECMMigration of tumor cells

Invasion Sequence of Basement Membrane by Tumor Cells

TheMETASTATIC CASCADE

Mechanism of metastasis development within a primary tumor

ResumeTumor growthTumor cells do not necessarily proliferate more rapidly than their normal counterpartThe major determinant of tumor growth is clearly the fact that more cells are produced than die in a given time

ResumeThe growth of cancerTumor growth rates may be expressed as doubling timeTumor angiogenesis refers to the sprouting of new capillariesTumor dormancy accounts for interval before the appearance of metastasis

ResumeTumor dormancyOften, metastatic tumors is not detectable at the time of the removal of a primary tumorBreast cancer and melanoma metastasis may remain dormant for many yearsIt is not known whether they remain in G0 phase of cell cycle for prolonged period of time or whether they do not grow because interference with angiogenesis, unrespon-siveness to growth factors, or the presence immune growth restraints

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