It can be readily calculated that the original transformed cell (approximately 10 μm in diameter) must undergo at least 30 population doublings to produce 109 cells (weighing approximately 1 gm), which is the smallest clinically detectable mass.
In contrast, only 10 further doubling cycles are required to produce a tumor containing 1012 cells (weighing approximately 1 kg), which is usually the maximal size compatible with life.
These are minimal estimates, based on the assumption that all descendants of the transformed cell retain the ability to divide and that there is no loss of cells from the replicative pool. This concept of tumor as a "pathologic dynamo" is not entirely correct, as we discuss subsequently.
Nevertheless, this calculation highlights an extremely important concept about tumor growth: By the time a solid tumor is clinically detected, it has already completed a major portion of its life cycle. This is a major impediment in the treatment of cancer, and underscores the need to develop diagnostic markers to detect early cancers.
The rate of growth of a tumor is determined by three main factors: the doubling time of tumor cells, the fraction of tumor cells that are in the replicative pool, and the rate at which cells are shed and lost in the growing lesion. Because cell-cycle controls are deranged in most tumors, tumor cells can be triggered into cycle more readily and without the usual restraints. The dividing cells, however, do not necessarily complete the cell cycle more rapidly than do normal cells. In reality, total cell-cycle time for many tumors is equal to or longer than that of corresponding normal cells. Thus, it can be safely concluded that growth of tumors is not commonly associated with a shortening of cell-cycle time.
The proportion of cells within the tumor population that are in the proliferative pool is referred to as the growth fraction. Clinical and experimental studies suggest that during the early, submicroscopic phase of tumor growth, the vast majority of transformed cells are in the proliferative pool.
As tumors continue to grow, cells leave the proliferative pool in ever-increasing numbers owing to shedding, lack of nutrients, or apoptosis; by differentiating; and by reversion to G0. Most cells within cancers remain in the G0 or G1 phases. Thus, by the time a tumor is clinically detectable, most cells are not in the replicative pool. Even in some rapidly growing tumors, the growth fraction is only about 20% or less.
Ultimately the progressive growth of tumors and the rate at which they grow are determined by an excess of cell production over cell loss. In some tumors, especially those with a relatively high growth fraction, the imbalance is large, resulting in more rapid growth than in those in which cell production exceeds cell loss by only a small margin.
Some leukemias and lymphomas and certain lung cancers (i.e., small cell carcinoma) have a relatively high growth fraction, and their clinical course is rapid. By comparison, many common tumors such as cancers of the colon and breast have low growth fractions, and cell production exceeds cell loss by only about 10%; they tend to grow at a much slower pace.
Several important conceptual and practical lessons can be learned from studies of tumor cell kinetics:
Fast-growing tumors may have a high cell turnover, implying that rates of both proliferation and apoptosis are high. Obviously, for the tumor to grow, the rate of proliferation should exceed that of apoptosis.
The growth fraction of tumor cells has a profound effect on their susceptibility to cancer chemotherapy. Because most anticancer agents act on cells that are in cycle, it is not difficult to imagine that a tumor that contains 5% of all cells in the replicative pool will be slow growing but relatively refractory to treatment with drugs that kill dividing cells. One strategy employed in the treatment of tumors with low growth fraction (e.g., cancer of colon and breast) is first to shift tumor cells from G0 into the cell cycle. This can be accomplished by debulking the tumor with surgery or radiation.
The surviving tumor cells tend to enter the cell cycle and thus become susceptible to drug therapy. Such considerations form the basis of combined modality treatment. Some aggressive tumors (such as certain lymphomas) that contain a large pool of dividing cells literally melt away with chemotherapy and cures may even be effected.
How long does it take for one transformed cell to produce a clinically detectable tumor containing 109 cells?
After they become clinically detectable, the average volume-doubling time for such common killers as cancer of the lung and colon is about 2 to 3 months. As might be anticipated from the discussion of the variables that affect growth rate, however, the range of doubling time values is extremely broad, varying from less than 1 month for some childhood cancers to more than 1 year for certain salivary gland tumors. Cancer is indeed an unpredictable disorder.
In general, the growth rate of tumors correlates with their level of differentiation, and thus most malignant tumors grow more rapidly than do benign lesions. There are, however, many exceptions to such an oversimplification. Some benign tumors have a higher growth rate than malignant tumors.
Moreover, the rate of growth of benign as well as malignant neoplasms may not be constant over time. Factors such as hormonal stimulation, adequacy of blood supply, and unknown influences may affect their growth. For example, the growth of uterine leiomyomas (benign smooth muscle tumors) may change over time because of hormonal variations. Not infrequently, repeated clinical examination of women bearing such neoplasms over the span of decades discloses no significant increase in size.
After menopause, the neoplasms may atrophy and may be replaced largely by collagenous, sometimes calcified, tissue. During pregnancy, leiomyomas frequently enter a growth spurt. Such changes reflect the responsiveness of the tumor cells to circulating levels of steroid hormones, particularly estrogens. Cancers show a wide range of growth. Some malignant tumors grow slowly for years and then suddenly increase in size, explosively disseminating to cause death within a few months of discovery.
It is possible that such behavior results from the emergence of an aggressive subclone of transformed cells. At the other extreme are malignant neoplasms that grow more slowly than do benign tumors and may even enter periods of dormancy lasting for years. On occasion, cancers have been observed to decrease in size and even spontaneously disappear, but such "miracles" are rare enough that they remain curiosities.