Chapter 11 Chapter 11 The Building Will Fall: Subverting Normal Growth Control

Over the past decade, people have managed to piece together a complete picture of cellular signaling systems.The outline of the system holds the key to unlocking the uncontrolled growth of cells that leads to cancer in humans.It also allows us to link out-of-control growth with the activity of certain genes.Proto-oncogenes and oncogenes lay out the blueprint of the system, directing the actions of a component -- a signal transduction protein.When the genetic blueprint is intact, the entire signaling system works smoothly and the cells make accurate decisions about growth and dormancy.However, if mutations compromise this blueprint, some parts of the system will malfunction, disrupting the entire decision-making process.Cancer is a disease caused by errors in the processing of information in the central cell.

We have already explored one consequence of disrupted signal processing systems: the growth of cancer cells is thus freed from the usual dependence on exogenous growth stimulators.The tumor protein set itself free by a small trick.They activate signal processing systems by mimicking the signals released by normal cells when they encounter growth factors.In effect, the tumor protein fools the cell into thinking it encounters the growth factor molecule. There are several different ways that tumor proteins carry out this trick.One class of oncoproteins coaxes cancer cells to release growth factors into the immediate external environment.This may seem like a no-brainer move, but these factors may actually go back and stimulate the cell that just released them, causing that cell to grow.By encouraging cells to make their own growth factors, oncogenes and their protein products free cells from dependence on exogenous growth factors.In effect, these oncogenes reengineer cells by making them continue to stimulate their growth.There is clear evidence that many types of human tumors release large amounts of PDGF and EGF into the surrounding environment.

Genes that regulate growth factor receptors also have a non-negligible role in the origin of cancer.Malfunctioning receptors can mislead cells into thinking they are in a sea of ​​growth factors when in fact there isn't one.At this time, the cells will continue to grow. There are at least two situations in which receptor function is impaired.Proto-oncogenes encoding growth factor receptors can mutate, changing the shape and structure of the receptor molecule.Even if the deformed receptor molecule does not encounter any growth factors, it will release a steady stream of growth-stimulating signals to the cell.Some breast cancer cells, for example, make a truncated EGF receptor that keeps fanning the flames in the absence of EGF.

Some human cancer cells have an unusually large number of receptor molecules.When the receptor molecules on the surface of a cell are unusually dense, they clump together and release signals spontaneously.This approach is remarkably effective at prompting cells to multiply.For example, when breast cancer cells express abnormally high levels of the EGF receptor and another related receptor called erbBZ/neu, the cells grow so recklessly that no medicine is effective.EGF receptors are also overexpressed in neurofibromatosis (brain tumors) and gastric cancer, which also induce cancerous growth of cells.

There is another way for cell growth to get rid of the conventional dependence on exogenous growth factors, and that is the dysfunction of ras protein.As noted above, normal ras proteins sit quietly in the cytoplasm awaiting signals from growth factor receptors.After receiving a signal from the receptor, ras quickly enters a state of stress, sending a stimulus signal deep into the cell.Soon after, it calmed down and returned to a still state.Such calming ensures that downstream signaling systems receive only limited growth-stimulating signals. The protein made by the ras oncogene behaves subtly differently from normal ras protein.Like ras proteins, ras oncoproteins are activated by and respond to a growth factor receptor, signaling to downstream target proteins in the signaling cascade.But the difference is that the proteins created by oncogenes do not have the ability to self-heal.It remains active for an indeterminate period of time, sending waves of growth-stimulating signals to the cells until they flood the cells.

The normal MPC gene makes a protein that sits in the nucleus and tricks other growth-promoting genes into action.Without foreign growth factors, cells can barely make the myC protein.But within an hour of encountering a growth factor, the cell is able to churn out large amounts of the myC protein, enabling the cell to read a lot of information that is critical to its growth The mpC oncogene behaves very differently from the normal proto-oncogene. The myC oncogene is always highly active, driving cells to grow even in the absence of growth factors. The oncogene form of the Zhouyc gene is found in many human tumors.Some cancers achieve persistent, dense expression by increasing the number of copies of the mpC gene.The number of c)C genes contained in certain types of tumor cells is not the proposed two, but dozens.The presence of a large number of copies of the yC gene appears to free myC from its usual regulation, allowing it to be highly and persistently expressed.In other cancer types, the mpC gene is fused to another gene that exerts unnatural control over the expression of mpC.In both cases, myC activity was no longer dependent on growth factor stimulation as usual.As a result, the high density of mpC protein production drives the cells to grow continuously.

A close relative of the mpC gene, monmyC, plays an important role in a type of childhood cancer.Early stages of childhood neuroblastoma, a tumor of the peripheral nervous system.In relatively benign cases, the number of N-msc genes in cells remains unchanged, with only 2 copies.However, as the tumor progresses, the number of copies of the -mpC gene will increase to 10, 20, or even 100 copies per cell.The incremental copies of these genes appear to be directly related to the continued expansion of tumors.The increased number of N-myC genes in neuroblastoma cells even became a significant indicator of treatment failure.Communication breaks: Loss of tumor suppressor protein

The signaling systems activated by the oncogene proteins are the same ones normally activated by cells in response to external growth factors.However, oncoproteins continuously activate signaling systems and allow cells to proliferate without any external growth-stimulating signals. But the role of oncogenes is only half the story.Tumor suppressor genes are also important in tumor development.As mentioned earlier, the tumor suppressor gene and its encoded protein are lost during the multistep process of tumor development, acting as brakes on cell proliferation.This reverse regulation mechanism is completely opposite to the function of oncogenes.

How do tumor suppressor proteins normally work in cells?To some extent, their functions can also be described simply like tumor proteins.A tumor receives two types of growth-regulatory signals from its environment -- both those that stimulate growth and those that inhibit growth.The signal processing mechanisms by which cells respond to inhibitory signals are as complex as those that respond to stimulatory signals.Many tumor suppressor proteins serve as components in mechanisms that respond to external growth inhibitory signals.Without the tumor suppressor protein, cells cannot properly respond to inhibitory signals.Even when the external environment yells it to stop, the cells continue to proliferate.

Mutations in the cell once again disrupt the communication between the cell and its environment.At this point, instead of enhancing the function of the tumor suppressor gene, the mutation inactivates or disables its function.Although the study of tumor suppressor genes is in its infancy and not much is known about the functions of many suppressor proteins, some facts are beginning to emerge.Like oncoproteins, suppressor proteins always exert their effects on the nucleus from many places on the cell surface.Here are a few very interesting examples of tumor suppressor effects. On the surface of cells, there are a series of receptors that allow cells to sense growth inhibitory signals.Among the growth-inhibitory signals, the signal carried by TGF card (tumor growth factor-p) has been studied most thoroughly.Like growth-stimulating factors, TGF levels are also composed of protein chains released by cells, wandering in the intercellular space, affecting a target cell, and the target cell responds by stopping growth.

Many tumor cells appear to escape growth inhibition by TGF cards.Unlike normal cells, these cancer cells were remarkably oblivious to the presence of TGF+; they continued to grow despite growth conditions severely inhibited by TGF++. Virtually all cells have specific receptor molecules on their surface that sense the presence or absence of TGF-10 in the surrounding fluid. TGF receptors are structured much like growth factor receptors.One end of them protrudes into the outer space of the cell and crosses the cell membrane, while the signal release structure at the other end penetrates deep into the cell interior. Several types of cancer cells appear to have lost the TGF receptors they should have.For example, although the reasons for the loss of these receptors in cells of retinal gliomas are unclear, the loss has a significant growth benefit for the cells.Normal retinal cells encounter a large amount of TGF-β in the fundus.Due to the lack of suitable receptors, retinal glioma cells are very forgetful about TGF-p, and ignore its stop command. The exact mechanism of loss of TGF receptors in HNPCC patients is well understood.They had a mutation in a gene that is the blueprint for a TGF receptor.This gene is compromised due to a defect in the cellular DNA repair machinery in HNPCC patients. Improper DNA repair disturbs the DNA sequence of the TGF-p receptor gene, so that the coding receptor loses its function.Colon cancer cells, like retinal glioma cells, were insensitive to TGF-β inhibition.Because tumor cells also face a Darwinian competition for the survival of the fittest, dodging inhibitory signals is of great benefit to tumor cells. The NF-1 tumor suppressor gene is unique in controlling cell growth.Individuals who inherit defective NF-1 develop neurofibromatosis, a disease characterized by numerous benign growths all over the body, some of which deteriorate.On the path that the ras protein transmits growth-stimulating signals, a protein is also involved, and this protein is regulated by the NF-1 gene.In this way, tumor suppressor proteins seem to be at a loss.However, only a deep analysis of the role of NF-1 protein can resolve the contradiction: the role of NF-1 protein is to calm the ras protein. After the growth factor receptors activate the ras protein, NF-1 attacks the ras protein halfway, and before the ras gets a chance to release the growth-stimulating factor, NF-1 deactivates it.This pre-emptive attack on the signaling pathway suppresses growth-stimulating signals within the cell.Without the NF-1 protein, an excess of growth-stimulating signals floods the nucleus, prompting the cell to proliferate. There are other suppressor proteins in the nucleus, including those made by the gene 16, Rb, p53, and the WT-1 tumor suppressor gene.The role of the first three proteins above is similar to the brakes in the cell cycle clock described later; the expression of cellular genes controlled by the WT-1 protein has yet to be determined.The exact mechanism of action of other tumor suppressor proteins is currently unknown. Tumor suppressor proteins are as diverse as the previously described oncogene proteins.The places where arrestins work are located in different corners of the cell.They inhibit cell growth through many different molecular mechanisms.But they all have one feature in common: the loss of any one of the inhibitory proteins in the cells results in an inability to properly respond to growth-inhibitory signals.Cells continue to thrive and grow when they must stop growing immediately. It appears that proto-oncogenes and tumor suppressor proteins form two parallel sets of distinct signaling systems in normal cells, one dedicated to promoting growth and the other to suppress it.Such a description, as tempting as it is, is misleading.In fact, these two types of proteins are the same components that play both positive and negative roles, and together constitute a signaling system.Inside the system, these two types of proteins check and balance each other, command properly, and relax, so that cells can participate in the construction and maintenance of normal tissue buildings.