Cancer is not an absolutely lethal disease, it is only a local symptom of the systemic lesion, and it is easy to treat and recover. Then why has cancer become an incurable disease and "the number one killer of human beings and the most difficult problem of modern medicine"? The three major mysteries of cancer are drug tolerance, tumor metastasis and the role of non-tumor tissues, which are also the three major dilemmas faced by medical research on cancer worldwide.
Drug resistance issues
In 1996, Charles Sawyers, a clinical oncologist at Memorial Sloan Kettering Cancer Center in New York, led an early clinical trial of a drug targeting cancer cell-specific mutations, imatinib (Gleevec), for the treatment of chronic lymphocytic leukemia, and Sawyers' clinical study found that the drug was highly effective in treating . Unfortunately, once tolerance to this drug is developed, the tumor cells return. This is a revolution in medical technology by identifying the cause of mutations in disease genes and designing targeted drugs. Targeting only the genetic mutation to treat tumors is not a universal model, though, because a very small percentage of malignancies have a cause as simple as leukemia. Gleevec has proven to be a surprise, and this strategy is only effective against a small number of tumors.
Biologists now know much more about malignancy than they did 10 years ago, and 500 genetic mutations have been identified in association with malignant tumorigenesis, and the number is growing. There are about 100 oncologic therapeutic drugs approved for gene mutations that have been marketed and have joined surgical resection and radiation therapy as the three main methods of treating cancer. This new treatment approach has achieved more desirable results, and the trend of increasing mortality from malignant tumors has been curbed to some extent in some regions.
About 50% of malignant tumors can be prevented by improving lifestyle eating habits and exercise, and it is also important to quit smoking and reduce environmental pollution. In order to control malignant tumors, scientists must answer some basic scientific questions, the first of which is how to deal with the problem of drug resistance in cancer cells. To overcome the drug resistance of cancer cells, scientists are studying the genome of cancer cells, proposing new drug design options, using combination of drugs, and even looking at Darwin's theory of evolution to find solutions to the problem. From an evolutionary perspective, a tumor is an ecosystem with a wide variety of genetically mutated cell types. Drug therapy is to give a relatively strong environmental selection pressure to these complex tumor cell populations. According to Darwinian evolutionary theory, many tumor cells die and some cells survive by using various survival strategies, which is called survival of the fittest. There are many strategies for tumor cells to tolerate drugs, such as generating protein pumps that expel drugs from the cell, accelerating the efficiency of DNA repair, or using alternate molecular pathways to replace drug-blocked cellular functions.
A comprehensive understanding of the genetic diversity of tumor cells may help scientists find ways to combat drug tolerance. But a more serious challenge is that some oncogenic mutations are expressed by silencing oncogenes, and it is a more difficult technique to activate such unexpressed genes as opposed to blocking the molecules that are present. The structures of many tumor-associated proteins are still unknown, and it is difficult for chemists to come up with a solution to the problem until the molecular structures are understood. In addition, there are many unknown tumor-associated proteins that have not been discovered, which makes a solution even less likely.
An important mode of malignant tumorigenesis is genetic mutation. On the one hand, most of the physicochemical factors that promote tumorigenesis can induce genetic mutations; on the other hand, there are indeed many malignant tumors in which genetic mutations are clearly present. However, one of the complexities of malignant tumors is that normal tissues surrounding malignant tumors also have an assisting role in tumor development, which not only challenges the understanding of the causes of malignant tumorigenesis, but also creates confusion and problems in controlling malignant tumors.
Mina Bissell, a bioengineer at Lawrence Berkeley National Laboratory, focuses on tumor-free tissues that are distributed around tumors, known as the tumor microenvironment, an area that has been neglected by the field of drug research in the past. Signals from the tumor microenvironment can limit the mutation of already malignant cells, and even cancer cells placed in such a microenvironment can be converted to benign. Jacqueline Lees of the MIT Koch Institute for Integrative Cancer Research agrees that the tumor microenvironment is important, and that it is incomplete to consider only the direct killing of cancer cells while ignoring the tumor microenvironment that causes the cells to become cancerous, and that there are interactions between tumor and non-tumor cells, tumors and the immune system, and that tumors do not survive on their own without support from the surrounding tissue cell microenvironment, which traditional Drug studies completely ignore this issue.
The most important cause of death in patients with malignant tumors is tumor metastasis. Epidemiological surveys show that 90% of tumor patients die from tumor metastasis. Tumor metastasis is complex, occurring either quickly or slowly, sometimes even 10 years after the patient has been definitively cured. Therefore, a deeper understanding of the mechanisms of tumor metastasis will facilitate the search for ways to prevent patient deaths.
Today, the process by which tumors begin to metastasize is becoming more recognized. Some cells in the tumor growth process are very active and can enter the blood circulation. Tumor cells that enter the blood circulation can settle in other tissues and organs and form new tumor bodies. The most mysterious aspect of this process is how these cells adapt and survive in their new environment. For example, brain and bone marrow tissues are completely different types of tissues from breast tissues, but it is surprising that tumor tissues can take root there. The glucose, oxygen concentration, and pH of these tissues may be very different from the primary tissues. In the primary tissues, tumor cells have access to supportive information such as growth factors and protein signaling; how do metastatic tumor cells obtain these supports? Scientists speculate that this adaptive capacity relies mainly on gene expression regulation rather than gene mutation. Even more incredible is that these metastatic tumor cells can remain in peaceful coexistence with surrounding tissues for up to 10 years at the metastatic destination in the process between arrival and the start of proliferation.
There are several other difficulties in the study of metastases. Once metastases are identified, patients are often in poor physical condition, collecting biopsy specimens is difficult, and the value of resecting the tumor is often small, which is one of the difficulties in metastasis research. Metastases are often small and difficult to identify with conventional clinical imaging techniques. Even when drugs have been developed to target metastatic tumors, the current clinical research paradigm makes it difficult to determine their therapeutic efficacy. Clinical studies tend to recruit patients with advanced or metastatic tumors, but strategies to control metastases in such patients have been completely irrelevant and unlikely to yield effective results.
In order to treat patients with tumors that have metastasized, it is important to understand the mechanisms by which tumors metastasize. First, scientists must understand which cells in tumor tissue are capable of metastasis and how the characteristics of these cells differ from those of other tumor cells. Some scientists have developed a method to identify cells of tumor origin by isolating 100 tumor cells from a primary tumor specimen, then cloning these cells, sequencing and labeling each clone, and injecting the cells into mice. Those cells with metastatic properties will grow tumors, and once these cells have formed tumors in the animal's body, these tumors are cut out and genetically characterized to determine which cells they are, and then those such cells that are being cultured are studied in comparison to those that are not metastatic to determine the differential characteristics of metastatic tumor cells and non-metastatic tumor cells.
Another approach is to isolate tumor cells from the patient's blood. These tumor cells in the circulation may hold the secret of the tumor's ability to metastasize, as there are necessarily cells among these cells that can metastasize. After isolation of such tumor cells, they can be studied by sequencing, imaging and gene expression analysis to compare with the primary tumor cells and obtain the characteristics of metastatic tumors.
In conclusion, despite the difficult road to cure cancer, scientists are still optimistic about overcoming cancer, after all, many problems that were not even thought of in the past have now been proposed and overcome.