Understanding the Mechanisms of Cancer

Virtually all major advances against cancer, including the newer molecularly targeted therapies, immunotherapies, and interventions to prevent cancer, had their origins in earlier discoveries made in the basic sciences. Many of these discoveries were made in areas such as cell biology, molecular biology, genetics, and immunology, where practical applications to cancer medicine could readily be conceived. Other areas, such as physics, mathematics, materials science, and computational sciences, have also helped to advance cancer research. Although cancer-related applications of discoveries in these latter areas were less immediately obvious in most cases, they contributed to the development of the advanced technologies and analytical methods that are essential to cancer research and clinical oncology today.

NCI’s funding of basic research has led to major advances in cancer genomics, which has enabled the development of new precision medicines and other approaches for cancer prevention, detection, and treatment. Yet, our knowledge of other fundamental mechanisms of cancer remain much less complete. For example, we need to increase our understanding of how normal cells become cancerous, how the tumor microenvironment influences cancer development and progression, how cancers evade attacks by the immune system, and the role of aging in cancer. Achieving a better understanding of these mechanisms will only be possible through additional basic research.

One of the best ways NCI supports basic research is through research project grants, which fund the vast majority of investigator-initiated science. The knowledge gained from this research will drive tomorrow’s advances to help patients with cancer and individuals at risk of the disease.

Progress in Understanding the Mechanisms of Cancer

Acquiring a comprehensive understanding of the molecular changes that drive the development and progression of malignant tumors has been a long-sought goal in cancer research. A major step toward this goal was achieved by The Cancer Genome Atlas (TCGA), a program jointly sponsored by NCI and the National Human Genome Research Institute, which is also part of NIH.

TCGA determined the major molecular characteristics of 33 of the most common types of cancer through an in-depth analysis of tumor specimens from more than 10,000 patients. The findings from TCGA have led to a new understanding of cancer at the molecular level and expanded tumor classification beyond the organ or tissue type to include cancer subtypes based on their molecular features (e.g., the four major molecular subtypes of female breast cancer: luminal A, luminal B, triple-negative basal-like, and HER2-expressing).

The Cancer Genome Atlas determined the major molecular characteristics of 33 of the most common types of cancer.

TCGA data are publicly available for further analyses through NCI’s Genomic Data Commons (GDC), one of multiple repositories that will allow NCI to build a Cancer Research Data Commons. Information from TCGA and from other research has also informed the design of newer research programs, such as the NCI Molecular Analysis for Therapy Choice (NCI-MATCH) and NCI–Children’s Oncology Group Pediatric MATCH clinical trials.

Other NCI-funded research has provided an initial understanding of how communication between cancer cells and other cells in the body contributes to cancer cell growth, how the plasticity of cancer cells can lead to their becoming resistant to specific treatments, and how cancer cells and immune cells interact to either promote or suppress tumor growth and progression. A few notable recent accomplishments on the mechanisms of cancer are described below.

Comparing the Molecular Features of Different Cancers

Comparing the molecular characteristics of different types of cancer can provide a better understanding of their similarities and differences and improve tumor classification, both of which will inform the development of new treatments and future clinical trials. In 2018, a consortium of international and NCI-funded researchers reported the results of a cross-tumor-type analysis of TCGA data and the corresponding clinical information.

The findings from this massive undertaking fell into three main categories: 1) cell-of-origin patterns, 2) oncogenic processes, and 3) cell signaling pathways. In the first category, the data suggest that different tumor types can be clustered according to the type of cell from which they are thought to have originated, a finding that increases our understanding of how the tissue in which a cancer arises can influence its molecular characteristics. The data in the second category provide a broad view of the molecular processes at the genomic level that drive cancer development and progression. Finally, the data in the third category detail the alterations in cell signaling pathways that cancer cells use to support their continued growth and survival.

Overall, this work will aid in the development of new treatments for a wide range of cancers. Read about how childhood cancer survivor Zach from Pennsylvania has benefited from a treatment that targets alterations of the ALK gene, which occur in more than one cancer type.

Why invest in basic science infographic
Progress against cancer requires long-term investments in basic research, which lay the foundations for tomorrow's clinical advances. Research that leads to a new treatment or intervention usually involves a process that spans years or even decades before patients benefit. The development of the cancer drug crizotinib (Xalkori) is one such example. Crizotinib was initially developed to target the protein produced by the oncogene MET. It was later found to also inhibit the proteins produced by oncogenic forms of the ALK gene, which have been found in anaplastic large cell lymphomas (ALCL) and some non-small cell lung cancers (NSCLC) and neuroblastomas. NCI-funded basic research identified these targets and revealed their biological importance in cancer development and progression. The arc of scientific discovery leading to the first Food and Drug Administration approval of crizotinib for NSCLC spanned a period of nearly 30 years. Clinical testing of the drug for additional molecular subtypes of NSCLC, ALCL, and neuroblastoma continues today.

Investigating How Cancer Cells Communicate with Normal Cells

Research has shown that cancer cells communicate with nearby normal cells and frequently co-opt some of their functions to support tumor growth and progression. However, a detailed understanding of the communication channels and mechanisms used by cancer cells is needed. NCI funding is helping to advance research in this area.

In 2017, an international team of NCI-funded investigators at Cold Spring Harbor Laboratory in New York and their colleagues demonstrated that pancreatic tumors induce different physiological responses from fibroblasts (connective tissue cells) that are closest to them than from fibroblasts that are farther away. They also showed that this pattern of responses was maintained when the locations of the fibroblasts were switched. The researchers concluded that the fibroblasts closest to a tumor are influenced by direct interactions with cancer cells, whereas fibroblasts farther away are influenced by factors secreted from cancer cells that diffuse toward them. Fully understanding these short-range communication mechanisms may reveal vulnerabilities that can be exploited therapeutically to block tumor growth.

In another NCI-funded study conducted in mice and humans, researchers showed that signals sent by lung tumors via the bloodstream trigger the migration of a certain class of neutrophils (white blood cells) from the bones to the tumors, where they exhibit cancer-promoting properties. Acquiring a detailed understanding of this long-distance communication mechanism may also reveal opportunities to disrupt tumor growth.

Identifying Elements that Suppress Antitumor Immunity

Antitumor immune responses are carried out primarily by cytotoxic T lymphocytes, or killer T cells. The activity of these cells can be inhibited in a variety of ways as part of normal regulation of the intensity and duration of immune responses. However, some of these normal inhibitory mechanisms can be co-opted by tumors to help cancer cells evade immune destruction.

Recently, scientists in NCI’s intramural research program discovered that two essential elements in the tumor microenvironment, namely oxygen and potassium, can be exploited to suppress cytotoxic T-cell activity. T cells of all types contain oxygen-sensing proteins called PHD proteins. When elevated amounts of oxygen are present, as in the lungs, the activity of these proteins creates an immunosuppressive environment that promotes tumor growth. Correspondingly, the dead and dying cells within tumors release potassium into the tumor microenvironment, increasing the extracellular concentration of this element, which suppresses cytotoxic T-cell activity. Ongoing research is focused on developing strategies against these and other mechanisms that inhibit antitumor immune responses.

Ongoing research is focused on developing strategies against mechanisms that inhibit antitumor immune responses.

Exploring the Biology of Fusion Oncoproteins

Fusion proteins are created by the joining, or fusion, of two separate genes that encode different proteins. They are commonly found in cancer, especially in childhood cancers, and they often drive tumor development. When fusion proteins contribute to tumor formation, they are called fusion oncoproteins. Because of their important role in driving cancer development, understanding the biology of these oncoproteins and finding ways to inhibit their activities is a major priority in cancer research, as well as a goal of the Cancer Moonshot℠.

In 2017, NCI-funded researchers at the University of Texas Health Science Center in San Antonio reported findings from a study of the fusion oncoprotein EWS-FLI1, which drives approximately 85% of Ewing sarcomas. These tumors occur mainly in children and young adults and are found most often in the bones.

The researchers discovered that EWS-FLI1 increases tumor cell production of an enzyme called pappalysin-1 (PAPPA), which breaks down certain proteins called insulin-like growth factor binding proteins (IGFBPs). The breakdown of IGFBPs releases the hormone insulin-like growth factor into the local environment, where it promotes cancer cell growth.

Using cell and animal models, the researchers also showed that inactivating PAPPA might be an effective strategy in treating Ewing sarcoma. Increased funding for basic research on this and other fusion oncoproteins should lead to new treatment approaches for pediatric and adult cancers.

Opportunities for Greater Progress

Advances in biomedical and computing technologies are giving us the tools to greatly increase our understanding of cancer biology. For example, scientists can now image and study individual structures and molecules inside cells, including living cells, at unprecedented levels of resolution. Despite these advances, there is still much more that we need to learn. Enhanced focus on the following areas of opportunity will enable greater progress against cancer.

Advances in biomedical and computing technology are giving us the tools to greatly increase our understanding of cancer biology.

Creating Four-Dimensional Maps of Human Tumors

Tumors are ecosystems that contain a variety of cell types, including cancer cells, immune cells, tumor-associated normal cells (fibroblasts, or stromal cells), vascular cells, and neural cells. These ecosystems evolve continuously during tumor development, progression, and in response to treatment.

In addition, the cancer cells in separate regions of a single tumor can differ from one another in important ways—a phenomenon known as tumor-cell heterogeneity—and both cellular and noncellular components of a tumor’s microenvironment can influence a tumor’s behavior (e.g., its aggressiveness or its responsiveness to treatment).

Given the need for a more comprehensive understanding of the molecular, cellular, and tissue alterations that drive cancer’s development and progression, the Cancer Moonshot is supporting the Human Tumor Atlas Network to construct detailed maps, or atlases, of the various components of tumors and their interactions over time for specific pediatric and adult cancers.

The Pre-Cancer Atlas, which is described in this plan in Preventing Cancer, is part of this effort. In addition to providing important insights into the initiation and evolution of tumors, these atlases will also inform the development of new approaches to cancer prevention and treatment.

Cancer and the human tumor atlas network infographic

Investigating the Role of Microbiomes in Cancer

Populations of bacteria, fungi, and viruses—collectively known as microbiomes—inhabit the skin, colon, mouth, and other tissues of the body, as well as some types of tumors. Some members of these microbial populations have been implicated in cancer development and in the effectiveness of cancer treatments. For example, NCI-supported researchers and others have shown that the composition of the intestinal microbiome can influence a tumor’s response to immunotherapy and that the bacteria in some pancreatic cancers can inactivate the chemotherapy drug gemcitabine (Gemzar).

There is still much more to learn about how microbiomes influence cancer-related processes, immune responses, and the effectiveness of cancer treatments. Specifically, we need to identify the relevant microbial species and the mechanisms by which they exert their effects. In the future, we may be able to modify the compositions of microbiomes to reduce cancer risk and optimize the effectiveness of cancer treatments without causing additional adverse effects.

Understanding Aging and Cancer

The greatest risk factor for cancer is advancing age. Accordingly, several processes associated with aging have also been linked with cancer development, including reductions in DNA repair capacity and immune function, a decline in the regenerative capacity of stem cells to replenish the body’s tissues, and the accumulation of nondividing, metabolically active (i.e., senescent) cells in tissues, which may secrete factors that promote chronic inflammation.

Additional support for research on the basic mechanisms of aging and cancer will enhance our understanding of both subjects and enable the development of new strategies for cancer prevention and treatment, as well as the optimal delivery of cancer interventions based on a person’s age. A critical unmet need in this area of research is the development and use of age-appropriate animal models. Studies to examine the effects of aging on the efficacy and toxicity of current cancer therapies are also a high priority to ensure that contemporary cancer patients can be stratified, as needed, to receive age-appropriate care, which may necessitate the development and administration of different treatment approaches for older patients.

Research on the basic mechanisms of aging and cancer will enable the development of new strategies for cancer prevention and treatment.

Defining the Role of Nuclear Architecture in Cancer

The term nuclear architecture refers to the structural organization, including the compartmentalization, of the components of a cell’s nucleus. This architecture is both complex and dynamic, changing as needed to carry out and regulate vital processes in the nucleus, such as DNA replication, DNA repair, and RNA transcription and processing. Defects in genomic organization and nuclear architecture have been linked to numerous human diseases, including cancer, neurodegenerative disorders, and muscular dystrophies, and they recently have been associated with human aging.

The development of advanced microscopy and imaging technologies, such as high-throughput chromosome territory mapping (HiCTMap) and Fourier phase-based depth-resolved nanoscale nuclear architecture mapping (nanoNAM), is providing new opportunities to investigate genomic organization and nuclear architecture at unprecedented levels of resolution. This research will lead to a greater understanding of both normal physiological processes and disease at the cellular level, and it may also identify important new targets for future cancer therapies. Additional funding will accelerate progress in this area.

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