Cancer cells follow predictable path to malignancy

Researchers at Stanford Medicine have made a groundbreaking discovery regarding the early stages of cancer development. They found that cells destined to become cancerous undergo a series of specific genetic changes in a predictable and sequential manner, even years before they can be identified as pre-malignancies. These genetic alterations primarily affect pathways that control cell division, structure, and internal communication, thereby setting the stage for future cancerous growth.

This study represents the first comprehensive examination of the natural evolution of early-stage human cancers. It commenced with cells carrying a single cancer-causing mutation and concluded with a panel of descendant cells harboring numerous genetic abnormalities.

By identifying the initial steps associated with future cancer development, the researchers believe that earlier diagnoses could be made, potentially preventing the deadly outcome. Furthermore, this research may shed light on new interventions that can halt the progression of the disease.

Dr. Christina Curtis, a professor at Stanford and the senior author of the study, expressed the goal of identifying a minimal combination of genetic alterations that indicate a cell’s progression towards cancer. By doing so, they hope to intervene and prevent the full development of cancer. The researchers observed highly consistent patterns of genetic changes across multiple donors, indicating the possibility of achieving this objective.

The research, published in Nature on May 31, was led by Dr. Kasper Karlsson and Moritz Przybilla, former postdoctoral scholar and visiting graduate student, respectively.

Cells of nefarious beginnings

Building on prior research in Dr. Curtis’s lab, the latest study delves into the early stages of cancer development, focusing on the behavior of colon cancer cells. The researchers discovered that certain colon cancer cells possess the ability to metastasize well before the disease becomes detectable.

Observations of established tumors revealed that early genetic alterations appear to shape the subsequent progression of the disease, with many of these changes occurring prior to tumor formation. This prompted the researchers to investigate the earliest stages of cancer cell evolution and determine if the evolutionary path is consistent and repeatable.

To conduct their study, the researchers utilized human stomach cells called gastric organoids, obtained from individuals undergoing gastric bypass surgery for obesity treatment. At the outset, the cells were manipulated to simulate cancer by inhibiting the production of the p53 protein, a key factor associated with cancer. Mutations in p53 are recognized as an early event in various human cancers, triggering the accumulation of additional genetic changes such as mutations and copy number alterations.

Over a span of two years, the researchers meticulously documented the genetic changes occurring in the dividing cells every two weeks. Analysis of the data revealed that while the changes transpired randomly, those conferring greater fitness bestowed an evolutionary advantage upon the host cells within the organoid. Through successive rounds of mutation and competition as the cells continued to divide, common themes began to emerge.

By conducting this study, the researchers aimed to shed light on the consistent patterns of genetic changes that occur during early cancer development. This knowledge could pave the way for identifying interventions that disrupt or prevent the progression of cancer at its earliest stages.

Predictable pathways

According to Dr. Curtis, the study revealed consistent and reproducible patterns in the genetic changes occurring during early cancer development. Specific regions of the genome consistently underwent loss shortly after the inactivation of p53, and this pattern was observed across different experiments and donors. These changes were found to be inherent to the cells themselves, indicating their role in tumor evolution. However, at the microscopic level, the cells and organoids appeared mostly normal and had not yet progressed to cancerous states.

The early genetic changes primarily affected biological pathways that regulate cell division, internal signaling networks, and cell structure and polarity. These alterations disrupted the cell’s ability to coordinate its functions and maintain tissue integrity. The researchers observed similar patterns across cells from different donors, suggesting the existence of constrained pathways guiding cancer progression. Some of these changes mirrored mutations previously observed in stomach cancer and Barrett’s esophagus, a pre-cancerous condition affecting the lining of the colon and stomach.

The study revealed a level of predictability in the genomic and transcriptomic levels, offering insights into the origins of these cancers. Dr. Curtis and her colleagues plan to replicate the study using different cell types and initiating events other than p53 mutation. They aim to understand the concept of malignant transformation and the early genetic events in various organs. Additionally, they want to investigate the interplay between the host and the environment, exploring the potential role of inflammatory factors in promoting cancer progression. The communication between cells within organoids is seen as crucial for understanding cancer progression and treatment responses.

The research involved contributions from scientists at Karolinska Institutet, University College London, and the Chan Zuckerberg Biohub.

Source: Stanford University Medical Center

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