Question

In this chapter, we focused on cancer as a genetic disease, with an emphasis on the relationship between cancer, the cell cycle, and DNA damage, as well as on the multiple steps that lead to cancer. At the same time, we found many opportunities to consider the methods and reasoning by which much of this information was acquired. From the explanations given in the chapter, (a) How do we know that malignant tumors arise from a single cell that contains mutations? (b) How do we know that cancer development requires more than one mutation? (c) How do we know that cancer cells contain defects in DNA repair?

Short answer

Malignant tumors arise from a single cell with mutations due to evidence from clonal origin studies, which analyze the genetic and biochemical markers of individual cells within a tumor. These studies show that all tumor cells have common genetic and biochemical traits, suggesting that they are descendants of a single mutated cell. Experiments on mouse models also support this theory, as single mutated cells transplanted into healthy mice led to the formation of tumors. (b) How do we know that cancer development requires more than one mutation? Cancer development requires more than one mutation, as evidenced by the multi-hit hypothesis. Cancer incidence increases with age, indicating that multiple mutations accumulated over time are necessary for cancer development. Experiments on mouse models have shown that cancer development requires mutations in multiple genes, including oncogenes and tumor-suppressor genes. Furthermore, diseases like colorectal cancer show a stepwise accumulation of mutations in their progression. (c) How do we know that cancer cells contain defects in DNA repair? Cancer cells are known to contain defects in DNA repair due to the high rate of mutations observed in cancer genomes. Individuals with inherited defects in DNA repair genes have a higher risk of developing cancer. When cells are exposed to carcinogens, their DNA repair systems may become overwhelmed, leading to an increased chance of developing cancer. Defects in specific DNA repair pathways can also be directly observed in certain cancer types, such as microsatellite instability in colorectal cancer due to defects in mismatch repair. Tumor cells lacking functional DNA repair mechanisms have a higher mutation rate, promoting tumor growth and progression.

Step-by-step solution

(a) How do we know that malignant tumors arise from a single cell that contains mutations?)

Malignant tumors are formed from the uncontrolled growth and division of cells, which is due to accumulated mutations. One way to determine that malignant tumors arise from a single cell with mutations is through clonal origin studies. These studies analyze the genetic and biochemical markers of individual cells within a tumor, showing that all tumor cells have some common genetic and biochemical traits. This suggests that all of the cells within the tumor are descendants of a single mutated cell, which underwent uncontrollable growth and division, eventually leading to the malignant tumor. This theory is further supported by experiments on mouse models in which a single mutated cell was transplanted into a healthy mouse and the formation of a tumor was observed.

(b) How do we know that cancer development requires more than one mutation?)

The concept that cancer development requires more than one mutation comes from the multi-hit hypothesis, which is supported by various lines of evidence. First, cancer incidence increases with age, indicating that the accumulation of multiple mutations over time is necessary for cancer development. Second, experiments on mouse models have shown that cancer development requires mutations in multiple genes, including oncogenes and tumor-suppressor genes. These different mutations act together to promote uncontrolled cell growth and division. The multi-step nature of cancer development can also be observed in diseases like colorectal cancer, where the progression of the disease involves the accumulation of mutations in a stepwise fashion.

(c) How do we know that cancer cells contain defects in DNA repair?)

The fact that cancer cells contain defects in DNA repair is inferred from the high rate of mutations observed in cancer genomes. Individuals with inherited defects in DNA repair genes tend to have a higher risk of developing cancer, providing a clear link between impaired DNA repair and cancer. Additionally, when cells are exposed to carcinogens (cancer-causing agents), their DNA repair systems may become overwhelmed, leading to the persistence of DNA damage and an increased chance of developing cancer. Furthermore, defects in specific DNA repair pathways can be directly observed in certain cancer types, such as microsatellite instability in colorectal cancer resulting from defects in mismatch repair. Tumor cells that lack functional DNA repair mechanisms often have a higher rate of mutation, which in turn promotes tumor growth and progression.

Key concepts

Clonal Origin of Tumors

Understanding the genesis of tumors is crucial when studying cancer. A common origin characterizes most malignancies, in what is known as the 'clonal origin of tumors'. This means that malignant tumors begin from a single abnormal cell that undergoes multiple genetic changes, leading to uncontrolled growth and division. Analyzing the genetic markers within a tumor reveals that despite their number, the tumor cells share genetic similarities, implying that they are clones of an original mutated ancestor cell.

These findings are essential for developing targeted cancer therapies, as recognizing the common genetic background of tumor cells can aid in designing treatments that hit all cancerous cells effectively. Moreover, this concept highlights the importance of early detection and intervention, since the progeny of the initially mutated cell retain the potential for rampant division and growth.

Multi-Hit Hypothesis

Cancer is rarely the result of a single genetic anomaly. The 'multi-hit hypothesis' posits that multiple genetic mutations across various genes are necessary to develop cancer. Each 'hit', or genetic mutation, represents one step closer towards malignancy. This process often unfolds over an extended period, generally correlating with increased cancer risk as individuals age.

Genetic mutations can affect critical genes that regulate cell growth and division. These include oncogenes, which can propel cells towards a cancerous state when aberrantly activated, and tumor-suppressor genes, which normally keep cell proliferation in check but may contribute to cancer when inactivated. It's a complex process where multiple systems must fail, indicating why cancer is often associated with older age, as the probability of accruing multiple 'hits' increases over time. The implication for treatment is that therapies might need to target several pathways simultaneously to be effective.

DNA Repair Defects in Cancer

At the heart of many cancers is the issue of DNA damage and the subsequent inability to repair these genetic injuries. Normally, cells have sophisticated mechanisms for repairing DNA, but defects in these systems can lead to increased mutation rates, some of which might confer cancerous properties such as the ability to proliferate unchecked.

Entities like carcinogens can inflict DNA damage which, if not correctly repaired, can usher in mutations that nudge a cell towards cancer. Certain hereditary conditions exemplify this: for example, individuals with Lynch syndrome inherit faulty mismatch repair systems, giving rise to a higher likelihood of colorectal and other cancers. Recognizing DNA repair defects is pivotal for cancer prevention and for tailoring treatments that either rectify these repair mechanisms or exploit the cancer cells' vulnerabilities arising from their impaired ability to mend DNA.

Oncogenes and Tumor-Suppressor Genes

Diving deeper into the genetic landscape of cancer, oncogenes and tumor-suppressor genes are pivotal characters. Oncogenes are like the gas pedal of the cell, driving cellular growth and division. When mutated, they can become stuck in the 'on' position, pushing cells into a proliferative frenzy leading to tumorigenesis. In contrast, tumor-suppressor genes act as the brakes, normally halting cell division when conditions are unfavorable. Mutations here can disable these brakes, allowing unchecked cell division.

Genetic disruptions affecting either type of gene can upset the delicate balance between cell growth and death, key to maintaining healthy tissues. Awareness of these genes' roles in cancer underscores the need for personalized treatments, where the specific genetic alterations of a patient's tumor dictate the therapeutic strategy. For oncology students and practitioners alike, grasping the functions and interactions of oncogenes and tumor-suppressor genes is fundamental for understanding the molecular underpinnings of cancer and advancing towards cure-centered research.