Tumor cell kinetics

Presenter: Nasasira cosmas

Facilitator . Dr Nixon Niyonzima, M.B.Ch.B., M.Med.,
M.Sc., Ph.D.
• Definition
• Terminologies
• Why we study tumor grow and kinetics
• growth of human tumors
• Cell-cycle analysis
• Cell proliferation in normal tissues
• Cell proliferation in tumors
• Cell proliferation and prognosis
• Cell kinetics – the study of cells and their growth and division.
• Tumor cell kinetics – study of tumor cells and their growth and division.
This has led to understanding of cancer cells and developing chemo
therapeutic methods
 Terminologies
• Cell cycle time Tc – time taken for a cell to duplicate itself.
• Growth fraction GF – the percentage of cells within the tumour that are growing.
• Potential doubling time T pot – the time taken for a tumour to double in size
assuming no cells are lost.
T pot = Tc/GF
• Volume doubling time VDT – observed time a tumour takes to double in size.
• Cell loss factor CLF - the number of cells from the tumour that are lost either via
cell death or senescence
 Why do tumor cells grow???
• Tumors grow because the homeostatic mechanisms that maintain the
appropriate number of cells in normal tissues are defective, leading to an
imbalance between cell proliferation and cell death leading to expansion
of the cell population.
• The proliferative rate of tumor cells varies widely between tumors- high
rates of proliferation and slow rates of proliferation and some can be non-
proliferating
 Why is this information important??
The rate of cell proliferation in tumors may be an important factor in
determining:
1. The prognosis . if the cancer cells are dividing more rapidly, it means
the cancer is faster growing or more aggressive. The rate of cancer cell
proliferation can be estimated by doing a Ki-67 test or S-phase fraction
2. Response to therapy. The faster that cancer cells divide, the more likely
it is that chemotherapy will kill the cells, causing the tumor to shrink.
They also induce cell suicide (self-death or apoptosis)
 Growth of human tumors
• There is wide variation in growth rate, even among tumors of the same
histological type and site of origin.
• Tumors that are known to be responsive to chemotherapy (lymphoma,
cancer of the testis) tend to grow more rapidly than less-responsive
tumors.
• Lung metastases tend to grow more rapidly than the primary tumor in the
same patient ??
• Many internal tumors are unlikely to be detected until they grow to
approximately 0.5 to 1.0 g (∼10 to 13 mm in diameter) and tumors of this
size will contain approximately 500 to 1000 million(0.5 to 1.0 × 109)
cells.
• Tumors arise from a single cell and a tumor containing approximately 109
cells will have undergone approximately 30 doublings in volume prior to
clinical detection
• There is evidence (eg. for breast cancer) that the probability of seeding of
metastases increases with the size of the primary tumor, but the long
preclinical history of the tumor may allow cells to metastasize prior to
detection.
• Thus “early” clinical detection may be expected to reduce but not to
prevent the subsequent appearance of metastases
Tumor growth may be slow at very early stages of development
because:
• overcome immunological and other host defense mechanisms
• induce proliferation of blood vessels to support them
Deceleration of growth of large tumors is also observed probably as a
result of:
• increasing cell death and decreasing cell proliferation as tumor
nutrition deteriorates 15
Cell-Cycle Analysis
• Cell cycle- a series of events in a cell that lead to maturity and subsequent
division.
• Divided into 2 main phases- interphase and m phase
• Interphase-( G1phase or Gap 1,s phase, G2 phase 0r gap 2
• M phase-it’s a mitotic phase, divided into 4 phases ( prophase, metaphase,
anaphase, telophase)
 Cell Proliferation
in Normal Tissues
Rapidly proliferating cells are more susceptible chemotherapy and hence the
side effects of chemo are more common and pronounced in these cells. E.g
myelosuppression, mucositis, hair loss, sterility.
Acute effects of radiation injury are also observed in these tissues, because
irradiated cells often die when they attempt mitosis.

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 Cell Proliferation in Tumors

• The rate of cell proliferation is usually less than that of some cells
in normal renewing tissue(intestine or bone marrow)
• Thus, growth of tumors is not simply the result of an increased
rate of cell proliferation as compared to the normal tissue of
origin. Rather, there is defective maturation and the population of
malignant cells increases because the rate of cell production
exceeds the rate of cell death.
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• Information about the duration of the cell cycle and of its constituent phases in human
tumors is available from a few early studies.
• Ts- 12-24hrs
• Tc- 2-3days
• Tpot- 2-20days
• This implies that tumors have a low growth fraction. Thus low growth fraction may be a
factor that contributes to the relative resistance of human tumors to cycle-active
chemotherapy.
• It follows that the rate of cell loss(death or spread) in many human tumors is in the range of
75% to 90% of the rate of cell production
Studies of human tumors demonstrate considerable heterogeneity in mitotic indices (
ratio between the number of cells in a population undergoing mitosis to the total
number of cells in a population)within different parts of the same tumor. Reasons;
• inverse relationship between differentiation and proliferative rate.
• presence of genetically distinct clones of cells in a mature tumor.
• variability in nutrient availability within the tumor microenvironment. well-
nourished tumor cells close to blood vessels have higher levels of rapidly
proliferating cells than poorly nourished cells close to a region of necrosis
The presence of slowly proliferating cells at a distance from functional
blood vessels has implications for tumor therapy:
• Such cells may be resistant to radiation because of hypoxia (hypoxia
makes tumors resistant to radiation and some chemotherapy- induces
expression of growth factors, angiogenic factors)
• Poor response to chemo due to low proliferation rate and limited drug
access.
There is substantial evidence that most tumors;
• Most arise from renewal tissues
• Are clonal- express common genetic markers
• Contain a limited population of stem cells with the capacity
to regenerate.
• tumor cells with stem cell properties might be proliferating
rather slowly, similar to stem cells in bone marrow or at the
base of the intestinal crypts
 Cell Proliferation and Prognosis
• There is a higher chance of response to chemotherapy in malignancies
with a high proportion of proliferating cells.
• Malignancies with a high proportion of proliferating cells grow more
rapidly both in the absence of effective treatment and during regrowth
after partially effective therapy.
 REFERENCES
1. The basic science of oncology 5th Edition by Ian Tannock, Richard Hill,
Robert Bristow

2. Basic Radiotherapy physic and biology by David S. Chang, Foster D.

Lasley, Indra J. Das, Marc S. Mendonca, Joseph R. Dynlacht