Chapter 15 Chapter 15: The Road Ahead: Tumor Development

In the United States today, about 40 percent of people will develop cancer at some point in their lives, half of whom are curable, and the other half will eventually die.In the mid-1990s, half a million lives were lost to cancer each year in the United States alone.In one sense, that number is staggeringly high.The human body seems too vulnerable in the face of such a vicious disease.But from another perspective, things are not so bad.One third of all cancer deaths are attributable to the consumption of tobacco products, especially cigarettes.One in ten deaths is caused by colorectal cancer, mainly caused by a poor diet, especially a high intake of meat and animal fats.By following a low-fat, low-meat diet and staying away from tobacco products, an American can cut his or her risk of dying from cancer in half, which means that the risk of dying from cancer is only one-tenth.Some epidemiologists are convinced that the risk can be reduced even more by strictly following a low-fat, vegetarian diet that includes plenty of fresh vegetables and fruits.

To many tumor biologists, a 10% risk of dying from cancer seems insignificant.This optimism stems from the following statistic: In a human lifetime of 70 years or more, the human body produces 10 cells, as many as the grains of sand in the Ganges River.These 10 cells will grow, divide, and go through their own cell cycle.Every division can be a catastrophe; the complexity of the cell cycle offers too many possibilities for catastrophe to emerge. Putting these numbers together, a very interesting insight can be derived: 10 people, each living a noble, healthy, impeccable lifestyle, will experience a total of 10'' cell divisions, but only 1 will die of cancer.Only 1 in 10 cell divisions is fatally cancerous.The ratio is not bad at all.

Throughout the book, we offer many explanations for this reassuring result.On the road where cells intend to form tumors, Guanshan blocks, and the human body sets up countless obstacles.It is these roadblocks that limit this deadly malady to extremely low levels. Cells must successively overcome these stumbling blocks and go through a complex multi-step process before they can successfully complete complete canceration.There are many kinds of obstacles.The most prominent is the cell's signaling system, which rejects all the chaos caused by the activation of an oncogene or the inactivation of a tumor suppressor gene.

The reason why a cell must go through multiple genetic changes to break away from its normal growth pattern lies in the subtlety and complexity of the cell signaling system.The system is carefully designed to resist imbalances due to a malfunction of a component.Thus, the activation of an oncogene or the inactivation of a tumor suppressor gene often has only a weak effect on cell reproduction. The road is long and long, full of dangers and obstacles.Even if an oncogene captures a cell successfully, it will still trigger the cell's apoptosis and suicide program, making the oncogene's dream come true.Even if the apoptosis is escaped through various strategies, there is still the threat of cell aging and crisis ahead; only when the cell passes through the crisis and breaks through the mortal barrier, can it and its offspring have a chance to form a fatal tumor.

But by this time, the road was not smooth.Many researchers believe that the immune system mounts a line of defense against tumor development.For example, there is a group of white blood cells called natural killer cells (NK), which seem to specialize in recognizing and destroying mutated cells.Although cell killing can be clearly seen when NKs and cancer cells encounter each other in a petri dish, it remains to be seen whether NK fighters can defend against tumors in living tissue. The potential anticancer function of NK cells still needs further research. The combination of barriers that thwart cancerous development forces the evolving precancerous cell to undergo multiple genetic changes, each designed to circumvent or outcompete this or that barrier.Each mutation, usually affecting a proto-oncogene or tumor suppressor gene, is a rare event.Because cancer requires the combined forces of many events, all of which are unlikely to occur in the average human lifespan, cancer monsters are usually difficult to run rampant.thirst for blood

Even if this small group of tumor cells makes it through without a hitch, other difficulties stand in the way.Like all human cells, the cells that form early tumors require adequate sources of nutrients and oxygen.At the same time, they must constantly remove carbon dioxide and metabolic waste. As long as a tumor cell population remains small—less than 1 millimeter in diameter—it can spread to solve the logistical problems of feeding and excreting.Molecules released by a cancer cell or its normal cellular neighbors can easily spread this short distance.However, once the cell clusters grow to a diameter of 1 mm, molecular diffusion becomes difficult.Now diffusion can no longer provide sufficient nutrients and oxygen to the cells, nor can it quickly remove waste products.Before long, the cell clusters are filled with excrement, and the cells are hungry and trapped.As mentioned earlier, these hypoxic cells often die from p53-induced apoptosis.

Cell death due to suffocation and metabolic intoxication approaches the rate of cell regeneration.Gains in cell proliferation are offset by attrition, so the volume of tumor cell clusters remains constant.Tumor cell populations may remain stagnant for years or even decades. Dividing and then dying of starvation or suffocation, the tumor cell population must break through this ineffective cycle to be fatal.To successfully break through, the cell team members must be highly creative: they must invent a better way to get nutrients and excrete waste. The answer is to develop your own blood circulation system.While this group of tumor cells is dying of starvation, its normal cell neighbors enjoy ample supply of nutrients and oxygen because of their close connection with the systemic circulatory system.Unlike tumor cell populations, normal tissues are densely populated with capillary networks.Such dense capillaries allow every cell in the tissue to have direct access to an adjacent capillary.These tiny channels, though only wide enough for a row of red blood cells to pass through, feed and remove waste from all active metabolic tissues throughout the body.

Capillaries are also made up of cells.This epithelial cell is adept at flexible body acrobatics, being able to lay flat on the body and then bend into a tube.These tubular cells connect end to end to form capillaries.Cells in normal tissues release specialized growth factors that stimulate epithelial cells to work and keep capillaries intact.If certain cells are starved of oxygen, they release vascular endothelial growth factor (VEGF), which prompts endothelial cells to proliferate and form new capillaries.Without this stimulus, epithelial cells would not laboriously form a cobweb of blood vessels in the spaces within the tissue.

To go beyond the 1mm diameter limit, cancer cell populations must figure out how to increase the number of capillaries inside.It took Boston surgeon Judah Folkman 20 years to figure out the tricks of cancer cells.Some members of the cancer cell cluster, mimicking the normal cells around them, have learned to secrete growth factors that attract endothelial cells from nearby tissues and prompt those endothelial cells to proliferate.Capillaries extend inside the cancer cell cluster, and finally, the tumor cell cluster has direct access to nutrient- and oxygen-rich blood.Now the population of cells can advance rapidly.Their long-cherished wish of multiplying for many years has finally come true after suffering setbacks.The number of cancer cells showed a breakthrough growth momentum.

Because the growth factors released by cancer cells stimulate the formation of blood vessels, which build channels for blood flow, they are often called "angiogenic factors."These factors include VEGF and bFGF (basic fibroblast growth factor).The ultimate victory of a tumor cell population is closely linked to its ability to stimulate blood vessel growth.As soon as members of the cell clusters begin to release large amounts of vascular growth factors, their progeny can form, within a few months, tumors densely packed with capillaries; these tumors can grow rapidly and expand widely.If a tumor does not possess a well-developed capillary network, it progresses much more slowly and patients generally have a better prognosis.Some physicians also judge the developmental stage of tumors and predict their future trends based on the presence or absence of dense capillary networks in tumor samples.

Exactly how tumor cells acquire this ability to generate internal blood vessels remains elusive.It is estimated that certain genetic mutations have occurred in the cells, causing an eruption of angiogenesis factors, which in turn pave the way for the long-term expansion of tumors.Sparks start a prairie fire The number of cells contained in a tumor mass 1 cm in diameter can reach as many as 1 billion.At first glance, this number is really too big.However, this number pales in comparison to the total number of human cells—the latter is 10,000 times larger than the former.Most deadly tumors are much larger. Fewer than 10 percent of cancer deaths are due to tumors that thrived in their original location.In most cases, it is the metastases that play the role of killer, that is, the expeditionary army of cancer cells that leave the primary tumor and set up camp elsewhere in the body.It is these new arrivals, or rather the new tumors inoculated by them, that are often fatal. The metastatic process that produces cancer cell colonies is extremely complex.First, the cells in the primary tumor must break through the barriers to their growth.These roadblocks are most pronounced in the tumor, constituting the largest part of the tumor mass.Cancer arises from the epithelial cells that line the cavities of many internal organs and the outer layer of the skin.There is a layer of protein structure network under the epithelial cell layer, which is the "basement membrane" that separates the epithelium from connective tissue and blood circulation.The basement membrane is the first roadblock encountered by cancer cells trying to leave the tumor parent. Under normal circumstances, it is difficult for cells to penetrate the intact basement membrane, and any attack that attempts to penetrate the basement membrane can only be initiated when the basement membrane is damaged.Tumor cells release enzymes that cleave the proteins that make up the basement membrane network.Once the basement membrane network collapses, tumor cells can gain access to the subcutaneous tissue.Here, they may also need to disintegrate cells to invade and destroy obstacles in their path. Cancer cell aggression relies on its ability to release proteases, which specialize in cleaving protein chains into smaller pieces.Like angiogenesis, secreting proteases is a trick that tumor cells learn later in the multistep process of tumor development.When normal cells form and repair normal tissue, proteases are used in the complex process of building tissue.As we speculated, the release and use of these proteases is tightly controlled.Expanding tumor cells subvert control and then abuse the proteases; instead of judging their doses, they let proteases flood their surroundings. Through pathological experiments, it is easy to find the increase of protease content in tumor tissue.As long as the surgeon gives a small piece of tumor tissue to the pathology laboratory personnel, they can predict the development trend of the tumor, which is their housekeeping skill.Like the presence of dense capillary networks, high concentrations of proteases in tumor samples do not bode well for patients.They imply that tumor cells have learned the tricks of destroying adjacent tissue and, as a result, may spread to farther and wider areas. In the initial small steps of invasion through the basement membrane, there is only minimal expansion of the tumor mass; in the case of epithelial tumors, the local tumor mass is called Carcinoma in situ.But the invading cell thus establishes a close connection with a network of highways leading to distant places.Some tumor cells used blood vessels as their migration route; others chose lymphatic vessels.In both cases, a single cell or a small cluster of cells breaks away from the tumor parent and drifts down the tube to land somewhere far away. These adventurers are almost always faced with a catastrophe.They must survive the rough waters of the circulatory system.They must climb the precipice of a lymphatic or blood vessel, burrowing through the tube's protective covering and into the underlying tissue.Once inside, these cellular pioneers must also manage to thrive in an environment that is alienated from all sides. Colon cancer migratory cells often settle in the liver.Breast cancer cells find their opportunity in bone.Lung cancer cells have the potential to metastasize to the brain.Every time they arrive in a new environment, these cell immigrants will face severe challenges, and they will encounter growth factors and unfriendly body structures. At this time, that is, in the late stage of tumor development, the genome of tumor cells has become extremely impetuous and unstable.This instability results in enormous genetic variability in the tumor cell population as a whole.New combinations of mutant genes are constantly being generated and tested.As in Darwin's theory of evolution, the few cells that happen to have particularly favorable genes will win the war.In the later stages of tumor development, mutated genes that can bring about the ability to invade or metastasize are extremely sought-after. Only a minority of tumor cells acquired these genes through random mutations.The vast majority of cell immigrants could not withstand the wind, frost, rain and snow on the long expedition and the harsh environment of their new homes, so their colonization attempts had to end in their own destruction.At this time, the tumor mother body has been greatly developed, enough to continuously send a large number of scouts to carry out such tasks.Pearls accumulate, water drips through stones, as long as we keep working hard, the almost hopeless mission will eventually be accomplished.So, somewhere far away, some new colony will eventually be established and grow.Sooner or later, these metastases begin to compromise the function of the host tissues in which they take root.Only at this time, the shadow of death will hang over the heads of cancer patients. Not much is known about how all these steps work.As metastatic cells flow through lymphatic vessels or blood vessels, they have certain receptor molecules on their surface that allow them to cling to the vessel walls.There are many types of these anchor receptors.Different anchor chains enable the transferred cells to associate with different molecular environments.The diversity and complexity of anchor receptors has hindered our understanding of how they operate. We still only have a partial understanding of metastases.The principles that guide the migration of most cancer cells are as mysterious as those that guide monarch butterflies.For cancer researchers, the progression of metastases remains uncharted territory, largely unexplored territory.