Name: how cancer cells spread to new sites
Uploaded: 2021-04-07T12:12:02.000Z
Duration: 2 min 30 s
Channel: JoVE

K12 Standards

Louisiana Student Standards for Science

High School

Life Sciences

from-molecules-to-organisms-structures-and-processes

From Molecules To Organisms: Structures And Processes

HS-LS1-4

Metastasis

Metastasis is a multi-step process, where the tumor cells overcome several challenges to spread from the primary site to form secondary tumors in the body. As few as one&#160; in a million cells manage to achieve metastasis.
Normal cells are confined to their tissue of origin by cell-cell adhesion and the basement membrane, which is a physical barrier present between tissues. Cancer cells overcome the tissue constraints by a process called epithelial to mesenchymal transition or EMT.
This transition activates two transcription factors, Snail and Twist, which promote the expression of genes involved in cell migration and down-regulate the cell-adhesion factors such as E-cadherin.
Transformed cells then penetrate the basement membrane by extending invadopodia, the actin-rich protrusions. Invadopodia secrete proteases, which degrade the basement membrane.
Once they are freed from the tissue constraints, the transformed cells reach the blood vessel by modifying the extracellular matrix.
Tumor cells then breakdown the basement membrane of the vessel and squeeze through the epithelial cells&#8217; tight junctions to enter the blood circulation by a process called intravasation.
The majority of the

metastasis

Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
<h4>Epithelial-to-Mesenchymal Transition</h4>
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-&#946;) or receptor tyrosine kinase (RTK) ligands, which further activate the transcription factors, such as zinc-finger proteins - Snail, Slug, Twist, and E47. These transcription factors bind to the promoter elements of genes encoding the adherens junction protein E-cadherin and downregulate them. They also recruit histone deacetylase (HDAC) to facilitate chromatin condensation and subsequent transcriptional repression of E-cadherins. Reduced E-cadherin expression results in reduced cell-cell adhesion, modulation of Rho GTPase function, and cell polarity loss, allowing cells to escape tissue constraints and enter the blood circulation.
Once the blood circulating cancer cell reaches a new site, the reverse process converts the mesenchymal-like circulating cells into tumor cells that can adhere to the new environment, leading to secondary tumor formation. This process is called mesenchymal-to-epithelial transition or MET.
<h4>Metastasis is a Chance Event</h4>
The cancer cells that intravasate into blood vessels have a minimal chance to survive and metastasize. The circulating tumor cells (CTC) in the blood and lymph are routinely neutralized by the immune cells (natural killer cells, monocytes/macrophages, and neutrophils). Although the survival rate of CTCs is low, there are several factors that aid cancer cells to survive during circulation. For example, blood platelets shield the CTCs against the binding of natural killer (NK) cells. Platelets also transfer MHC or major histocompatibility complex to CTCs, allowing cancer cells to escape immune surveillance. Cancer cells can also inhibit NK cell activity by downregulating the NKG2D immunoreceptor.
Given the complexity of metastasis and genetic heterogeneity among the tumor cell population, these factors collectively make cancer difficult to cure. Creating therapeutics and treatments that specifically target stages of metastasis may lead to the reduction of the incidence of cancer deaths.

Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) ...

Education

JoVE Core

Molecular Biology

Unit 2

Cancer

KEY TERMS AND CONCEPTS

how cancer cells spread to new sites

Metastasis is the spread of cancer cells from one part of the body to another. Cancer cells can move through blood vessels, called hematogenous spread, or through lymph vessels. This process helps form tumors in distant tissues.

A key step in metastasis is epithelial-to-mesenchymal transition, or EMT. EMT is a normal developmental process seen in wound healing and embryogenesis, but it also appears in cancer metastasis. It is triggered by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands.

These signals activate transcription factors such as Snail, Slug, Twist, and E47. These proteins turn down genes that make E-cadherin, a protein that helps cells stick together. They also recruit histone deacetylase, or HDAC, which condenses chromatin and further blocks E-cadherin production. When E-cadherin levels fall, cell-cell adhesion weakens, cell polarity is lost, and cancer cells can leave the tissue and enter the bloodstream.

After a circulating cancer cell reaches a new location, the process can reverse. This is called mesenchymal-to-epithelial transition, or MET. During MET, mesenchymal-like cells become tumor cells that can attach to the new tissue and form a secondary tumor.

Metastasis is also a chance event. Cancer cells that enter blood vessels have only a small chance of surviving long enough to spread. Circulating tumor cells, or CTCs, are often destroyed by immune cells such as natural killer cells, monocytes/macrophages, and neutrophils.

Some factors help CTCs survive in the blood and lymph. Blood platelets can shield CTCs from natural killer cells. Platelets can also transfer MHC, or major histocompatibility complex, to CTCs, which helps cancer cells escape immune surveillance. Cancer cells may also reduce NK cell activity by downregulating the NKG2D immunoreceptor.

Because metastasis is complex and tumor cells can differ from one another, cancer is difficult to cure. Treatments that target specific stages of metastasis may help reduce cancer deaths.

How Cancer Cells Spread to New Sites

what is cancer?

Cancer Cells and How They Spread

Cancer cells and how they spread are explained through the normal behavior of cells and tissues. In a healthy body, cells must coordinate carefully. They rest, grow, divide, differentiate, or die in ways that support the organism. Cancer begins when this control breaks down. Cells divide without stopping and invade nearby tissues or organs. Cancer cells show two heritable traits. They reproduce against normal limits on cell growth and division, and they invade and colonize other cells and...

cancers originate from somatic mutations in a single cell

cancers-originate-from-somatic-mutations-in-a-single-cell

How Mutations Drive Cancer Growth

Cancer develops when mutations change the genes that control the cell cycle and let healthy cells keep dividing. A cancer can begin from a single mutation in one starting cell. As that cell line keeps growing, it can collect more mutations and eventually become malignant. One example is chronic myelogenous leukemia, or CML. It often begins as a non-lethal rise in white blood cells and then grows worse over several years before becoming life-threatening. This shows how cancer can progress step...

tumor progression

From Polyp to Metastatic Cancer

Tumor progression is the stepwise change that can turn an early tumor into a more aggressive and malignant cancer. Foulds first described this pattern in the 1950s. Colon cancer is one of the best-known examples, because researchers can follow its changes over time. In colon cells, an early mutation in the APC gene can create a small growth on the colon wall called a polyp. Over time, this polyp may grow into a benign, pre-cancerous tumor. Later mutations in the K-ras and p53 genes can push...

adaptive mechanisms in cancer cells

How Cancer Cells Survive and Spread

Cancer cells survive and spread by gaining genetic changes that help them grow faster than normal cells. These changes build up quickly because defects in DNA repair let mutations appear at an unusually high rate. From an evolutionary point of view, this genetic instability gives cancer cells an advantage as they develop. As mutant cell lines keep changing, they collect helpful mutations that support cancer progression. These cells can divide without fully differentiating, form large cell...

the tumor microenvironment

How Tumors Remodel Their Surroundings

Tumors remodel the local tissue environment to support cancer growth. This surrounding area is called the stroma. It includes several cell types, a basal membrane, and blood vessels. As normal cells mutate and become cancer cells, the nearby environment changes with them. The tumor microenvironment, or TME, is made of the developing tumor and the stromal cells around it. Communication between cancer cells and these surrounding cells is important because it disrupts normal tissue balance and...

Metastasis is the spread of cancer cells from one part of the body to another. Cancer cells can move through blood vessels, called hematogenous spread, or through lymph vessels. This process helps form tumors in distant tissues. A key step in metastasis is epithelial-to-mesenchymal transition, or EMT. EMT is a normal developmental process seen in wound healing and embryogenesis, but it also appears in cancer metastasis. It is triggered by transforming growth factor-beta (TGF-β) or receptor...

cancer-critical genes i: proto-oncogenes

Oncogenes and Cell Growth Control

Genes usually make proteins that help healthy cells work properly. When mutations change how these genes are expressed, the cell’s traits can change too. If critical genes that control the cell cycle and growth signals are disrupted, cell cycle progress can go off track and cells may divide without control. Over time, these cells can form tumors. Cancer-critical genes are the genes that drive this process. They fall into two main groups: proto-oncogenes and tumor suppressor genes.

mechanisms of retrovirus-induced cancers

How Retroviruses Trigger Cancer

Retroviruses can trigger cancer by changing how host cells grow and divide. These RNA viruses have been shown to cause cancers in species such as chickens, mice, cats, and monkeys. After infection, the viral RNA genome is reverse-transcribed into DNA. It first becomes single-stranded DNA and then double-stranded DNA. This double-stranded form, called proviral DNA, integrates into the host genome. The host cell then transcribes the proviral DNA along with its own chromosomal DNA. This process...

the ras gene

Ras Proteins: Cellular Switches in Cancer

Ras proteins are small GTPase signaling proteins that help control cell proliferation, differentiation, and cell survival. In humans, the Ras gene family has three main members: HRas, NRas, and KRas. These genes produce four closely related proteins: HRas, NRas, KRas4A, and KRas4B. Ras proteins work like molecular switches. They cycle between an active GTP-bound form and an inactive GDP-bound form. Guanine nucleotide exchange factors, or GEFs, help exchange GDP for GTP and turn Ras on.

loss of tumor suppressor gene functions

Tumor Suppressor Genes and Cancer Risk

Tumor suppressor genes help protect cells from becoming cancerous. They can slow cell division, repair DNA mistakes, or trigger apoptosis, which is programmed cell death, when damage cannot be fixed. These jobs help stop damaged cells from multiplying. When a tumor suppressor gene mutates or is lost, cells may begin to grow out of control. A single working copy is usually enough for the cell to keep normal control of the cell cycle. Cancer develops when both copies are inactivated or lost. <br...

mtor signaling and cancer progression

How mTOR Drives Cell Growth in Cancer

mTOR signaling helps control cell growth by balancing building processes and breakdown processes. mTOR stands for mammalian target of rapamycin. It was discovered in 1994 because it binds directly to rapamycin. Its name also comes from a yeast protein called TOR. In mammalian cells, the mTOR protein complex responds to environmental cues such as nutrients and growth factors. It supports anabolic processes, which are the cell’s building steps. These include the synthesis of proteins, lipids,...

cancer stem cells and tumor maintenance

How Cancer Stem Cells Drive Relapse

Cancer stem cells help tumors survive treatment and return after therapy. These residual cells can remain after early diagnosis and treatment, and they often lead to tumor recurrence. They are important because they can self-renew and also produce more than one cell type, which makes them hard to eliminate. Cancer stem cells are thought to come from normal stem cells or progenitor cells in a tissue. Normal stem cells usually stay quiet, or quiescent, until a signal tells them to divide or...

mouse models of cancer study

Mouse Cancer Models in Drug Testing

Mouse cancer models help scientists study how tumors start, grow, and respond to treatment. Mice are widely used because they are similar to humans in many biological and body functions. They are also easy to keep and breed in the laboratory, so many inbred strains are available for research. Cancer research has made major use of genetically modified mice. Transgenic mice carry an added gene, while knockout and knock-in mice have genes deleted or changed with genetic engineering. If a gene...

cancer prevention

Diet and Exercise in Cancer Risk

Diet and exercise can play a major role in cancer risk. Studies show that about 50% of cancer cases may be prevented through a healthy lifestyle, regular exercise, and a modest cancer prevention diet. Populations that eat more fruits and vegetables tend to have lower cancer rates. In contrast, diets high in animal fat, red meat, junk food, or calories are linked with a higher risk of cancer. Plant compounds called phytochemicals may also help protect against cancer. These natural chemicals...

cancer therapies

Combining Cancer Treatments

Cancer treatments often combine surgery, radiation therapy, and chemotherapy. These methods are used to treat cancer patients, but they can also damage normal cells. Cancer cells can also change quickly and become resistant to chemical agents or radiation therapy. Not every cancer responds to the same therapy. Some cancer cells respond to one treatment, while others respond to another because they carry different mutations. The best treatment depends on the type of cancer and how far it has...

targeted cancer therapies

How Targeted Cancer Drugs Work

Targeted cancer drugs are designed to act on specific molecular features that help cancer cells grow and spread. They are also called molecular targeted therapies. These treatments depend on a detailed understanding of the differences between cancer cells and normal cells, so the drug can focus on the cancer cell’s driving signals without harming healthy cells as much. One major group is angiogenesis inhibitors. Angiogenesis means the formation of new blood vessels, which tumors use to get...

treatment resistant cancers

How Cancer Cells Resist Treatment

Cancer cells can resist treatment by changing how they respond to anticancer drugs. This resistance makes cancer harder to treat. It also helps explain why cancer remains a major health problem. Cancer is the second leading cause of death in the United States. Cancer cells are genetically unstable, so they can mutate quickly. They can also change their microenvironment, which helps them avoid immune surveillance. In many tumors, resistance develops when cells alter drug transport or drug...

combination therapies and personalized medicine

combination-therapies-and-personalized-medicine

Cancer Treatment Pairings and DNA-Guided Care

Combination therapy for cancer uses two or more treatments together to improve patient outcomes. This approach can extend life span and help protect vital organs and tissue from the damage that may come from using one treatment too much. It also attacks more than one cancer-causing pathway, which can lower the chance of treatment resistance. A clear example is the pair of acetazolamide and sulforaphane. Large tumors often have a low-oxygen, acidic center, and cancer cells respond by making...

cancer-critical genes ii: tumor suppressor genes

cancer-critical-genes-ii-tumor-suppressor-genes

How Tumor Suppressor Genes Prevent Cancer

Tumor suppressor genes help keep cell growth under control. They can slow cell division, repair DNA errors, or trigger apoptosis, which is programmed cell death. These jobs protect healthy cells and help maintain normal cell cycle progression. When a tumor suppressor gene is disrupted, cells can lose this control. Loss-of-function mutations in these genes can let damaged cells keep dividing. Over time, that unchecked growth can contribute to tumor formation and cancer. Most tumor suppressor...

the retinoblastoma gene

Retinoblastoma Gene and Childhood Eye Tumors

The retinoblastoma gene, or Rb, is a tumor suppressor gene linked to a rare eye cancer in children. Tumor suppressor genes are normal genes that help slow cell division, fix DNA mistakes, or trigger apoptosis, which is programmed cell death when damage cannot be repaired. These genes help protect the body from damaged cells growing out of control. Rb was the first tumor suppressor gene ever identified. It was discovered through study of retinoblastoma, one of the most common malignant tumors...

rous sarcoma virus (rsv) and cancer

How RSV Uses Src to Drive Tumor Growth

Rous sarcoma virus, or RSV, is a retrovirus that can trigger tumor growth in chickens. F. Peyton Rous first discovered it in 1911 as a filterable transmissible agent. His work showed that some cancers can be caused by infectious agents. He later received the Nobel Prize in 1966 for this discovery, which also helped lead to the finding of other cancer-causing viruses in animals and humans. RSV carries two copies of a plus-strand RNA genome. Its genome has four main open reading frames, or ORFs:...

key terms and concepts

Explore how cancer cells spread through blood and lymph, how EMT and MET help metastasis, and why immune evasion makes cancer harder to treat.

How Cancer Cells Spread to New Sites | JoVE K12

molecular biology

JoVE Core Molecular Biology showcases the molecular processes of the cell through clear and concise animated video lessons. Additionally, in scientist-in-action videos, these concepts' application is demonstrated through real experiments in modern laboratories.

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chromatin-position-affects-gene-expression

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Organization of Genes

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A functional eukaryotic chromosome must contain three elements: a centromere, telomeres, and numerous origins of replication.
The centromere is a DNA ...

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HS-LS1-1

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HS-LS1-2

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HS-LS1-3

How Cancer Cells Spread to New Sites

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