21.1 Hallmarks of cancer and oncogenic transformation
3 min read•july 22, 2024
Cancer cells are rebels with superpowers. They ignore normal growth rules, resist death, and trick the body into helping them thrive. These hallmarks of cancer make tumors tough to beat, as cells mutate and adapt to survive at all costs.
The is cancer's secret weapon. It's a complex ecosystem of cells and molecules that support tumor growth, help cancer evade the immune system, and even assist in spreading to new locations in the body.
Hallmarks of Cancer
Hallmarks of cancer cells
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- Sustain proliferative signaling by continuously dividing and growing achieved through activation of oncogenes (RAS, MYC) or inactivation of tumor suppressor genes (p53, PTEN)
- Evade growth suppressors by bypassing normal cell cycle checkpoints and growth inhibitory signals through inactivation of tumor suppressor genes (p53, RB)
- Resist cell death by evading apoptosis, a programmed cell death mechanism, through upregulation of anti-apoptotic proteins () or downregulation of pro-apoptotic proteins ()
- Enable by maintaining telomere length, allowing unlimited cell divisions through reactivation of or alternative lengthening of telomeres (ALT) mechanism
- Induce by stimulating the formation of new blood vessels to support tumor growth through secretion of pro-angiogenic factors (, )
- Activate by acquiring the ability to invade surrounding tissues and spread to distant organs through epithelial-to-mesenchymal transition () and matrix metalloproteinases ()
- Deregulate cellular energetics by altering metabolism to support rapid growth and proliferation through the Warburg effect: increased aerobic glycolysis even in the presence of oxygen
- Avoid immune destruction by developing mechanisms to evade the immune system through downregulation of MHC class I molecules or expression of immunosuppressive factors ()
- Promote inflammation in the tumor microenvironment which supports cancer progression through recruitment of immune cells that secrete growth factors and pro-angiogenic factors
- Accumulate genome instability and mutations, leading to increased mutational burden due to defects in DNA repair mechanisms and increased sensitivity to mutagenic agents
Process of oncogenic transformation
- Involves the accumulation of genetic and epigenetic alterations that cause normal cells to acquire cancerous properties
- Genetic alterations include activation of oncogenes through gain-of-function mutations (RAS, MYC) and inactivation of tumor suppressor genes through loss-of-function mutations (p53, PTEN)
- Epigenetic alterations include changes in DNA methylation, histone modifications, and non-coding RNA expression that alter gene expression without changing the DNA sequence
- Leads to the disruption of normal cell functions such as cell cycle regulation and differentiation
- Results in transformed cells exhibiting the hallmarks of cancer, such as uncontrolled proliferation and resistance to cell death
Genetic changes in cancer development
- are single nucleotide substitutions that can activate oncogenes or inactivate tumor suppressor genes
- are large-scale changes in chromosome structure such as translocations, deletions, and amplifications
- (CNVs) are changes in the number of copies of specific genes or genomic regions
- Genetic changes can be inherited () or acquired ()
- Accumulation of these changes over time leads to the progressive development of cancer
Role of tumor microenvironment
- Consists of various cell types and extracellular components surrounding the tumor
- include fibroblasts, endothelial cells, and pericytes
- Immune cells include (TAMs), T cells, and natural killer (NK) cells
- (ECM) includes collagen, fibronectin, and proteoglycans
- Supports tumor growth and survival through tumor-stromal interactions
- (CAFs) secrete growth factors and cytokines that promote tumor growth and angiogenesis
- Remodeling of the ECM facilitates tumor invasion and metastasis
- Immune cell infiltration can have both pro-tumor and anti-tumor effects
- TAMs often exhibit an M2-like phenotype, promoting tumor growth and immunosuppression
- Regulatory T cells () suppress anti-tumor immune responses
- Hypoxic environment in the tumor core stimulates angiogenesis and metabolic adaptations through activation of (HIFs)
- Engages in metabolic cross-talk with cancer cells, exchanging nutrients and metabolic byproducts such as lactate ()
Key Terms to Review (36)
Angiogenesis: Angiogenesis is the biological process through which new blood vessels form from pre-existing ones, crucial for supplying nutrients and oxygen to tissues. This process is not only vital for normal growth and development but also plays a significant role in various pathological conditions, particularly in cancer, where tumors exploit angiogenesis to secure their blood supply and facilitate their growth.
Avoiding immune destruction: Avoiding immune destruction refers to the ability of cancer cells to evade detection and elimination by the body's immune system. This characteristic allows tumors to grow and proliferate unchecked, contributing to the progression of cancer. By employing various mechanisms, such as downregulating surface antigens or secreting immunosuppressive factors, cancer cells can escape the surveillance of immune cells, facilitating their survival and expansion.
Bax: Bax is a pro-apoptotic protein that plays a critical role in the regulation of apoptosis, or programmed cell death. It is part of the Bcl-2 family of proteins and acts by promoting mitochondrial outer membrane permeabilization, which leads to the release of cytochrome c and other apoptotic factors. Bax's function is significant in the context of cancer, as its activity influences the balance between cell survival and death, thereby impacting oncogenic transformation.
Bcl-2: Bcl-2 is a protein that plays a crucial role in regulating apoptosis, or programmed cell death, by inhibiting the process. It is part of a larger family of proteins that either promote or prevent apoptosis, and its primary function is to block the release of cytochrome c from mitochondria, which prevents the activation of caspases and promotes cell survival. Understanding bcl-2 is essential for comprehending the delicate balance between cell death and survival, which is particularly significant in cancer biology.
Cancer-associated fibroblasts: Cancer-associated fibroblasts (CAFs) are a type of stromal cell that have undergone activation within the tumor microenvironment and play a crucial role in cancer progression. These fibroblasts contribute to tumor growth, invasion, and metastasis by altering the extracellular matrix, promoting angiogenesis, and supporting the survival of tumor cells. Their presence is linked to the hallmarks of cancer as they create an environment conducive to tumor development and support oncogenic transformation.
Chromosomal aberrations: Chromosomal aberrations are structural or numerical alterations in chromosomes that can lead to various genetic disorders and diseases, including cancer. These abnormalities can occur through mechanisms such as breaks, deletions, duplications, inversions, or aneuploidy, which can impact gene expression and cellular function. Understanding chromosomal aberrations is crucial because they are often linked to DNA damage and repair mechanisms, as well as the hallmarks of cancer and oncogenic transformation.
Copy Number Variations: Copy number variations (CNVs) are segments of DNA that vary in number from one individual to another, involving duplications or deletions of genomic regions. These variations can significantly impact gene dosage and expression, playing a critical role in various biological processes, including oncogenic transformation and cancer progression.
David Hanahan: David Hanahan is a prominent cancer researcher known for his contributions to understanding the molecular basis of cancer, particularly in relation to the hallmarks of cancer. His influential work, alongside Douglas Weinberg, introduced a framework that describes the key characteristics that enable tumor cells to thrive and proliferate, forming a basis for cancer biology and therapeutic strategies.
Deregulating cellular energetics: Deregulating cellular energetics refers to the disruption of normal metabolic processes within cells, particularly in how they produce and utilize energy. This phenomenon is often associated with cancer cells, which can alter their energy production pathways to support uncontrolled growth and survival, ultimately enabling them to thrive in low-nutrient environments. This metabolic shift plays a critical role in the hallmarks of cancer, allowing tumors to maintain their energy needs while evading traditional regulatory mechanisms.
EMT: EMT, or epithelial-mesenchymal transition, is a biological process where epithelial cells lose their characteristics and gain migratory and invasive properties to become mesenchymal stem cells. This transition is crucial in various biological processes, including embryogenesis, tissue repair, and fibrosis, and plays a significant role in the progression of cancer by enabling tumor cells to invade surrounding tissues and metastasize to distant sites.
Evading growth suppressors: Evading growth suppressors refers to the ability of cancer cells to ignore signals that normally inhibit cell division and growth. This characteristic is crucial in oncogenic transformation, as it allows cells to bypass the regulatory mechanisms that would typically prevent excessive proliferation. In a healthy context, these suppressors play a vital role in maintaining normal cellular functions, ensuring that cells grow and divide appropriately, thus preventing tumor development.
Extracellular matrix: The extracellular matrix (ECM) is a complex network of proteins and carbohydrates that provide structural and biochemical support to surrounding cells. It plays a crucial role in regulating cellular functions, influencing cell behavior, and facilitating communication between cells. The ECM is not only vital for maintaining tissue integrity but also for processes such as cellular differentiation, tumor progression, and the development of 3D cell cultures.
Fgf: FGF, or Fibroblast Growth Factor, refers to a family of proteins involved in various biological processes including cell growth, development, and tissue repair. These proteins play a crucial role in signaling pathways that contribute to oncogenic transformation by promoting angiogenesis, cell proliferation, and survival, which are key hallmarks of cancer.
Germline mutations: Germline mutations are alterations in the DNA that occur in the reproductive cells, which can be passed on to offspring. These mutations can be inherited from one or both parents and can have significant implications for genetic diversity and disease susceptibility, particularly in the context of cancer development and oncogenic transformation.
Harold Varmus: Harold Varmus is a prominent American oncologist and Nobel laureate known for his groundbreaking work in cancer biology, particularly regarding the discovery of oncogenes. His research has significantly advanced the understanding of how certain genes can drive the development of cancer, linking genetic mutations to tumor formation and providing insights into the hallmarks of cancer and oncogenic transformation.
Hypoxia-inducible factors: Hypoxia-inducible factors (HIFs) are transcription factors that play a crucial role in cellular responses to low oxygen levels, or hypoxia. When oxygen levels are reduced, HIFs become stabilized and activated, leading to the expression of genes that promote adaptation to low oxygen conditions, such as increased angiogenesis, altered metabolism, and enhanced cell survival. In the context of cancer, HIFs can significantly influence tumor growth and progression by enabling cancer cells to thrive in hypoxic environments.
Invasion and Metastasis: Invasion and metastasis refer to the processes by which cancer cells spread from their original site to other parts of the body. Invasion involves the direct penetration of cancer cells into surrounding tissues, while metastasis is the movement of these cells through the bloodstream or lymphatic system to establish secondary tumors in distant organs. These processes are critical in the progression of cancer, enabling tumors to grow beyond their initial location and contribute to the severity of the disease.
MMPS: Matrix metalloproteinases (MMPs) are a group of enzymes that play a crucial role in the breakdown of extracellular matrix components. They are essential for normal physiological processes like tissue remodeling and wound healing, but they also contribute to cancer progression by facilitating tumor invasion and metastasis through the degradation of the surrounding matrix.
Natural Killer Cells: Natural killer cells (NK cells) are a type of lymphocyte in the immune system that play a crucial role in the body's defense against tumors and viral infections. They are part of the innate immune response and can recognize and destroy compromised cells without prior sensitization, making them essential in identifying and eliminating early-stage cancerous cells.
Oncogenic transformation: Oncogenic transformation refers to the process by which normal cells are converted into cancerous cells, often due to genetic mutations and alterations that affect cellular growth and regulation. This transformation is characterized by the acquisition of specific traits that allow the cells to grow uncontrollably, evade apoptosis, and invade surrounding tissues. Understanding this process is crucial for recognizing the hallmarks of cancer, as it highlights how various cellular pathways can be disrupted, leading to malignancy.
PD-L1: PD-L1, or Programmed Death-Ligand 1, is a protein that plays a crucial role in regulating the immune system by inhibiting T-cell activation and promoting immune tolerance. This protein is often expressed on the surface of tumor cells, which can exploit it to evade detection and destruction by the immune system, contributing to cancer progression and survival.
Pi3k/akt pathway: The PI3K/AKT pathway is a critical signaling cascade involved in regulating cell growth, survival, and metabolism. This pathway plays a pivotal role in cellular responses to growth factors and hormones, contributing to processes such as cell proliferation and anti-apoptosis, which are vital in cancer development and progression.
Point mutations: Point mutations are changes in a single nucleotide base pair in DNA, which can occur through substitution, insertion, or deletion. These small alterations can have significant consequences on gene expression and protein function, often contributing to the development of diseases, including cancer. Understanding point mutations is crucial for grasping the mechanisms behind oncogenic transformation and how they affect tumor suppressors and proto-oncogenes.
Promoting inflammation: Promoting inflammation refers to the biological process that enhances the body's immune response to injury or infection, often characterized by redness, swelling, heat, and pain. This process is crucial in the context of cancer, as chronic inflammation can create an environment that supports tumor development and progression, influencing multiple aspects of oncogenic transformation.
Ras pathway: The ras pathway is a crucial signaling cascade that begins with the activation of Ras proteins, which are small GTPases, and plays a significant role in regulating cell growth, differentiation, and survival. This pathway is often mutated in various cancers, leading to uncontrolled cell proliferation and contributing to the hallmarks of cancer such as sustained proliferative signaling and evasion of apoptosis.
Replicative immortality: Replicative immortality refers to the ability of cells to divide indefinitely without undergoing senescence, a characteristic often seen in cancer cells. This phenomenon allows these cells to proliferate uncontrollably, contributing to tumor formation and progression. It is closely linked to mechanisms that evade the normal cellular limits of division, enabling the persistence of cancerous growths.
Resisting cell death: Resisting cell death refers to the ability of cells, particularly cancer cells, to evade the normal mechanisms of apoptosis (programmed cell death) and survive in conditions that would typically lead to their elimination. This characteristic is a fundamental hallmark of cancer, allowing tumor cells to persist, proliferate, and become more aggressive. By overcoming cell death signals, cancer cells can maintain their growth advantage and contribute to the development of tumors.
Reverse warburg effect: The reverse Warburg effect is a phenomenon where cancer cells promote aerobic glycolysis in surrounding stromal cells, leading to increased lactate production that cancer cells can then utilize as a fuel source. This process allows tumors to thrive in a nutrient-rich environment by hijacking the metabolism of nearby cells, highlighting the intricate relationship between cancer cells and their microenvironment.
Somatic mutations: Somatic mutations are changes in the DNA sequence that occur in non-germline cells after conception, meaning they are not inherited but can affect the organism's health and development. These mutations can accumulate in tissues over time, leading to various effects such as altered cell function, growth regulation, and ultimately contributing to the development of diseases, particularly cancer. Somatic mutations can provide a significant source of genetic diversity within an organism's body, but their role in oncogenic transformation is crucial as they can lead to the hallmarks of cancer.
Stromal Cells: Stromal cells are the supportive tissue cells found in various organs, playing crucial roles in maintaining the structure and function of tissues. They provide a supportive framework for the parenchymal cells (the functional cells of the organ) and are involved in various processes, including inflammation, tissue repair, and immune response. In the context of cancer, stromal cells can significantly influence tumor development and progression by interacting with cancer cells and altering the tumor microenvironment.
Sustaining proliferative signaling: Sustaining proliferative signaling refers to the ability of cancer cells to continuously signal themselves or neighboring cells to grow and divide, leading to uncontrolled proliferation. This characteristic is one of the hallmarks of cancer, highlighting how tumors can manipulate growth signals to avoid normal regulatory mechanisms, thereby enabling their own growth and survival.
Telomerase enzyme: Telomerase is a specialized enzyme that adds repetitive nucleotide sequences to the ends of chromosomes, known as telomeres. By extending these telomeres, telomerase plays a critical role in maintaining chromosomal stability and cellular longevity, which are essential factors in oncogenic transformation and cancer development.
Tregs: Tregs, or regulatory T cells, are a specialized subset of T cells that play a crucial role in maintaining immune system homeostasis and preventing autoimmune responses. They help suppress excessive immune reactions and ensure that the body's immune response is balanced, which is particularly important in the context of cancer, where uncontrolled immune responses can lead to tumor progression and metastasis.
Tumor microenvironment: The tumor microenvironment refers to the complex and dynamic environment surrounding a tumor, including various cell types, extracellular matrix components, signaling molecules, and blood vessels that interact with the tumor cells. This environment plays a critical role in tumor progression, influencing cancer cell behavior, growth, and metastasis while also contributing to the development of resistance to therapies.
Tumor-associated macrophages: Tumor-associated macrophages (TAMs) are a type of immune cell found within the tumor microenvironment, where they play a complex role in cancer progression and development. These macrophages can adopt various phenotypes, often skewing towards a pro-tumorigenic profile that supports tumor growth, metastasis, and immune evasion. Understanding the behavior of TAMs is crucial, as they are linked to several hallmarks of cancer, including sustained proliferative signaling and evasion of immune destruction.
VEGF: Vascular Endothelial Growth Factor (VEGF) is a signaling protein that plays a crucial role in angiogenesis, which is the formation of new blood vessels from pre-existing ones. This protein is secreted by cells, particularly under conditions of low oxygen (hypoxia), and promotes the growth of blood vessels, facilitating the delivery of oxygen and nutrients to tissues. VEGF is particularly important in the context of cancer, as tumors often exploit this pathway to enhance their own blood supply, supporting growth and metastasis.