Pathophysiology Ch. 10

For a cell to become cancerous, numerous mutations must occur in its (genes, enzymes) (simultaneously, over time).

genes; over time

Malignant tumors are (heterogeneous, homogeneous) in their cellular composition.

heterogeneous

Abnormal premalignant growths in epithelial tissues that have not crossed the basement membrane are called carcinoma ____.

in situ

Genomic instability refers to:

increased tendency for genome alterations and mutability during cell life cycles

Characteristics of cancer cells that enable them to survive and proliferate include loss of contact ___, resistance to apoptosis, and anchorage ____.

inhibition; independence

Malignant tumors in the colon most commonly metastasize to the (lungs, liver).

liver

What is the difference between a driver mutation and a passenger mutation?

A driver mutation is important for cancer progression, but a passenger mutation is a random mutation that presumably does not contribute to cancer progression.

What is the difference between a proto-oncogene and a tumor suppressor gene?

A proto-oncogene codes for proteins that stimulate cell proliferation, but a tumor suppressor gene codes for proteins that suppress cell proliferation.

What is the difference between a proto-oncogene and an oncogene?

A proto-oncogene is a normal gene that codes for proteins that stimulate cell proliferation appropriately, but an oncogene is a proto-oncogene that is mutated in such a way that its proteins are inappropriately active, accelerating cell proliferation.

A cancer cell that secretes growth factors that stimulate its own growth engages in ____ stimulation.

autocrine

What are the heritable changes in cells that contribute to cancer development?

Accumulation of small changes in the deoxyribonucleic acid (DNA) and chromosomes of a cell causes it to become cancerous. There are many ways that heritable changes in cells can contribute to cancer. These include small and large DNA mutations that alter genes, chromosomes, and non-coding RNAs, as well as epigenetic changes, because of altered chemical modifications of DNA and histones. These mutations also refer to heritable changes in gene and non-coding RNA expression, epigenetics, which do not involve changes in DNA sequence.

How is cancer diagnosed?

After tumor identification, tumor tissue is examined microscopically for histological hallmarks of cancer. This information will allow for staging and treatment planning.

Having no cellular differentiation

Anaplastic

Epigenetic modification silences an oncogene.

Anticancer effect

Point mutation inactivates proto-oncogene.

Anticancer effect

Write the letters in order: A. Cancer cells attach to vascular endothelium, attracted by tissue-specific characteristics and survival signals of a premetastatic niche. B. Tumor microenviornment drives cell dedifferentiation by epithelial-to-mesenchymal transition, with mutations that enable anchorage independence, increased motility, and secretion of proteases. C. Cancer cells circulate, evading the immune system by associating with platelets or other mechanisms. D. Cancer cells leave the blood vessel, facilitated by their motility characteristics and vascular remodeling. E. Cancer cells secrete chemical signals that co-opt local and circulating cells, creating a new microenvironment where they proliferate. F. Cancer cells move into a blood vessel, facilitated by leaky blood vessels created through angiogenesis.

B,F,C,A,D,E

Lipoma

Benign tumor of fat cells

Rhabdomyoma

Benign tumor of skeletal muscle

Leiomyoma

Benign tumor of smooth muscle

Identify the major differences between benign and malignant tumors.

Benign tumors are usually well encapsulated and well differentiated, retain some normal tissue structure, and do not invade the capsule. They also do not spread to regional lymph nodes or distant locations. Malignant tumors have more rapid growth rates and specific microscopic alterations, including loss of differentiation; absence of normal tissue organization; lack of a capsule; invasion into blood vessels, lymphatics, and surrounding structures; and distant spread (metastasis).

Why did Ms. Smith have a blockage in her airflow?

Bronchogenic carcinoma arises in the lining of the airways and can cause an obstruction as it grows inward into the lumen.

Why did Ms. Smith's physician order a liver scan when he discovered that Ms. Smith had bronchogenic carcinoma?

Bronchogenic carcinoma frequently metastasizes to the liver.

Why had Ms. Smith's cancer metastasized before she had enough signs and symptoms to seek out her physician?

Bronchogenic carcinoma usually does not cause symptoms in its early stages; by the time the cancer is discovered, the tumor may be advanced and there has been time for metastasis to occur.

How do cancers protect themselves from cell death?

Cancer cells are immortal. When they reach a critical age, cancer cells activate telomerase to restore and maintain their telomeres, thereby allowing cancer cells to divide repeatedly or become immortal. Like many normal adult tissues, cancers can contain rare stem cells that provide a source of immortal cells. To fully eradicate a cancer, it may be necessary to target the cancer stem cell.

Define epigenetics and epigenetic silencing.

Epigenetics refers to heritable changes in gene and non-coding RNA expressions that do not involve changes in DNA sequence. Epigenetic silencing refers to whole regions of chromosomes being shut off, so that the pattern of gene expression is different from that in other cells with the same genes. Silencing is caused by reversible chemical modification (methylation, addition of methyl group; acetylation, addition of acetyl group) of histones and related chromatin components, as well as methylation of cytosine residues in DNA known as DNA methylation.

Research has shown a connection between the development of cancer and the: (select all that apply)

Epstein-Barr virus hepatitis B virus hepatitis C virus human papillomavirus

Why is the tumor microenvironment important to cancer progression?

Cancer is a complex genetic disease, and the microenvironment of a tumor is a heterogeneous mixture of cells, both cancerous and benign. This environment supports the initial proliferation of cancer cells and enlargement of the tumor elicit the synthesis of proinflammatory mediators by the cancer cells and adjacent nonmalignant cells.

"My uncle has liver cancer and so does my mom," says Sandi Mauntz. "But the doctor said his cancer is primary and hers is metastatic. What does that mean?"

Cancer starts in one location, and then cancer cells can break off and travel to a new location, were they form another tumor, in a process called metastasis. The first place where cancer starts is called the primary tumor. So the cancer in your uncle's body started in his liver. The cancer in your mother's body started in another location, and cells from that primary tumor broke off and moved to your mother's liver. That is why her liver cancer is called metastatic.

What is carcinoma in situ?

Carcinoma in situ (often abbreviated CIS) refers to preinvasive epithelial tumors of glandular or squamous cell origin.

"I am grateful that I survived chemotherapy," says Mr. Gillespie. "I knew I would lose my hair, but I was surprised when I got those painful sores in my mouth. How did the chemo cause the sores?"

Chemotherapy drugs kill cells that are dividing rapidly. That kills cancer cells, but it also kills some normal cells like the cells in the lining of your mouth. So the drugs that helped get rid of the cancer also made those painful sores. Now that you are no longer receiving chemotherapy, your body has repaired the lining of your mouth.

(Acute, Chronic) inflammation predisposes to development of cancer.

Chronic

The process by which a cell develops a specialized organization and function.

Differentiation

Identify common viruses that can cause cancer.

Hepatitis B and C viruses, Epstein-Barr virus, Kaposi sarcoma herpesvirus, and human papillomavirus are associated with about 15% of all human cancers worldwide. Cancer of the cervix and hepatocellular carcinoma account for about 80% of virus-linked cancer. Chronic hepatitis B infections confer up to a 200-fold increased risk of developing liver cancer. Up to 80% of liver cancer worldwide is associated with chronic hepatitis. Virtually all cervical cancer is caused by infection with specific subtypes of herpesvirus, which infects basal skin cells and commonly causes warts. Epstein-Barr virus, the cause of infectious mononucleosis, infects B lymphocytes and stimulates their proliferation. In individuals who are immunosuppressed, persistent Epstein-Barr infection can lead to the development of B-cell lymphomas. Epstein-Barr infection is also associated with Burkitt lymphoma in areas of endemic malaria and with nasopharyngeal carcinoma, a cancer endemic in Chinese populations in Southeast Asia. Herpesvirus 8 is linked to the development of Kaposi sarcoma, a cancer that occurs in older adult men and in a markedly more virulent form in immunocompromised individuals and has also been linked to several rare lymphomas. Human T-cell leukemia-lymphoma virus is an oncogenic retrovirus linked to the development of adult T-cell leukemia and lymphoma.

Did Ms. Smith's lung cancer metastasize from cancer in another location in her body, or did it arise in her lungs? What information provides this answer?

Her cancer arose in her lung. The term bronchogenic means that the tumor arose in the bronchi.

Why does inflammation fuel cancer development/invasion?

In both cancer and inflammation, inflammatory cells are attracted to the area and release cytokines and growth and survival factors that stimulate local cell proliferation and new blood vessel growth. These factors combine in chronic inflammation to promote continued proliferation. Inflammatory cells release compounds such as reactive oxygen species (ROS) and other reactive molecules that can promote mutations and block the cellular response to DNA damage. Increased abundance of the enzyme, cyclooxygenase-2, which generates prostaglandins during acute inflammation, has been associated with colon and some other cancers.

Osteogenic sarcoma

Malignant bone tumor

Sarcoma

Malignant tumor arising from connective tissue

Carcinoma

Malignant tumor arising from epithelial tissue

Liposarcoma

Malignant tumor of fat cells

Adenocarcinoma

Malignant tumor of glandular epithelium

Rhabdomyosarcoma

Malignant tumor of skeletal muscle

What are the most common treatments of cancer?

Many types of cancers can be effectively treated with chemotherapy, radiotherapy, surgery, and combinations of these modalities. Alternative therapies can be biologically harmless or harmful; rarely is there any evidence they are medically effective, and in the worst cases they can be expensive, delay the use of effective therapies, and produce toxic side effects.

"I remember the oncologist telling my sister and me that our mother's cancer had spread to her liver. What was that fancy 'meta-' word that he used?" says Mr. Gillespie.

Metastasis. That means the cancer cells have traveled in the blood or the lymph and have formed a new tumor distant from the primary one. The liver is a common place for cancer metastasis.

a new growth

Neoplasm

Mr. Gillespie asks, "Does everybody who gets liver cancer have cancer someplace else first?"

No, cancer can arise in the liver, just as it can arise in the colon. Cancer arises when the genetic material in the cells develops mutations that cause the cells to multiply in an uncontrolled fashion and develop the characteristics of cancer cells.

Mr. Gillespie says, "I got so tired during the chemo. My doctor says I was anemic. Did the chemo kill off my red blood cells too?"

No, chemotherapy drugs usually do not kill red blood cells, but they can kill the rapidly dividing cells in your bone marrow that make the red blood cells. Normally, we make new red blood cells all the time to replace the old ones; during your chemo treatment, you were not making enough new red blood cells. Now that you have recovered, your bone marrow is able to make enough red blood cells.

"Now please explain the reverse Warburg effect," says Nurse Davidson. "Does that mean the cancer cells make glucose instead of burning it for energy?"

No, the reverse Warburg effect does not involve cancer cells making glucose. They need energy to fuel their rapid growth. The reverse Warburg effect involves tumor-associated fibroblasts using anaerobic metabolism to make high-energy chemicals that the cancer cells extract to use for fuel.

Why is the stroma important for cancer growth and invasion?

Normal tissues contain a complex mixture of cell types, including specialized cells, fibroblasts, vascular, immune cells, and a supporting extracellular matrix. Cancers disrupt this environment and, in turn, recruits local and distant cells to assist in cancer progression. Cancers actively recruit an immune and stromal response to assist in remodeling of tissues, formation of new blood vessels, and promotion of metastasis. The tumor-associated inflammatory cells and fibroblasts are stimulated by the cancer cells and the ensuing stromal disruption. These otherwise normal cells secrete a broad range of factors that promote proliferation, angiogenesis, and cancer cell motility. The cancers also may release signals that actively recruit circulating bone marrow-derived mesenchymal stem cells to populate the tumor stroma, subverting a process that normally functions in wound healing.

Why did Ms. Smith develop dyspnea ?

Obstruction to airflow because of the tumor in the airway and compression of lung tissue from an expanding tumor both can contribute to dyspnea in people who have bronchogenic carcinoma.

Define oncogene, proto-oncogene, and tumor-suppressor gene.

Oncogenes are mutant genes that direct synthesis of proteins that accelerate proliferation in their normal nonmutant state. In its normal, nonmutant state, an oncogene is a proto-oncogene. Tumor-suppressor genes encode proteins that in their normal state negatively regulate or halt cell proliferation; they also have been referred to as anti-oncogenes.

"My mother had a lot of pain, but the nurses managed the pain medications very well," says Mr. Gillespie. "What surprised me is that I did not have any pain except from the surgery and those mouth sores. Why didn't I have cancer pain?"

Pain usually does not occur until a cancer is advanced. Your cancer was detected early, before the tumor had grown big enough to put pressure on nerves or cause a lot of tissue destruction and inflammation.

Having variable size and shape

Pleomorphic

Describe the differences between point mutations, chromosomal translocations, and gene amplification in the process of cancer.

Point mutations are small-scale changes in DNA, the alteration of one or a few nucleotide base pairs. Chromosome translocations are large changes in chromosome structure, in which a piece of one chromosome is translocated or moved to another chromosome. Gene amplification is an intermediate- to large-scale genetic abnormality. Amplifications are the result of duplication of a small region of a chromosome over and over again, so that instead of the normal two copies of a gene, tens or even hundreds of copies are present.

Chromosome instability causes loss of both copies of tumor suppressor genes.

Procancer effect

Chromosome translocation creates Philadelphia chromosome.

Procancer effect

DNA methylation occurs in the promoter regions of both copies of a tumor suppressor gene.

Procancer effect

Decreased expression of specific noncoding RNAs causes increased expression of oncogenes.

Procancer effect

Gene amplification creates multiple copies of gene for epidermal growth factor receptor.

Procancer effect

Mutation disrupts caretaker gene.

Procancer effect

Point mutation inactivates one tumor suppressor gene, allele, epigenetic change silences the other.

Procancer effect

The normal (oncogene, proto-oncogene) ras becomes the (oncogene, proto-oncogene)ras when a mutation makes the RAS protein active all the time.

Proto-oncogene; oncogene

Mutations in (oncogenes, proto-oncogenes) that convert them to (oncogenes, proto-oncogenes) drive development of cancer by causing uncontrolled cell growth.

Proto-oncogenes; oncogenes

The lining of the bronchi normally is pseudostratified columnar epithelium, not squamous cells. Why did Ms. Smith's cancer develop from squamous cells?

Repeated exposure to cigarette smoke causes squamous metaplasia in the bronchi, which means that the normal pseudostratified columnar epithelial cells are replaced with squamous cells that can survive more easily in the harsh environment. One or more of these squamous cells eventually accumulated enough mutations to become malignant.

Mr. Winslow has small cell carcinoma of the lung, with persistent hyponatremia. "The doctor told me that cancer cells are making a hormone and said 'paraneoplastic syndrome,' but then her beeper rang and she had to leave in a hurry," says Mrs. Winslow. "Please finish the explanation. What hormone? What does paraneoplastic syndrome mean?"

Some cancers release substances into the blood that cause effects elsewhere in the body. Those effects are called paraneoplastic syndromes. Your husband's cancer cells release a substance called antidiuretic hormone (ADH) into the blood that is causing a paraneoplastic syndrome. Normally, the pituitary gland releases ADH, but feedback controls keep it from making too much ADH. The cancer cells do not have feedback controls, so they keep releasing too much ADH.

(PIC)Does assigning the TNM numbers grade or stage the cancer?

Stage

(PIC) Write the TNM numbers for a woman with breast cancer that has metastasized to her lungs, has invaded her chest wall, and has involved several fixed lymph nodes.

T3 N2 M1

(PIC) What do these letters represent? T-____ N-_____ M-_____

T= tumor (size and extent of tumor) N= nodes (lymph node involvement) M= metastases (extent of distant metastases)

Define telomeres, telomerase, and senescence and describe their effects on cancer.

Telomeres are protective ends found on each chromosome and are placed and maintained by a specialized enzyme called telomerase. Senescence is the cessation of cell division. Short telomeres normally signal the cell to cease cell division (senescence).

What is cancer?

The National Cancer Institute (NCI) of the National Institutes of Health (NIH) defines cancer as "diseases in which abnormal cells divide without control and are able to invade other tissues."

"What is the Warburg effect?" says Nurse Davidson, who is reading a journal article about new cancer treatments. "What does that mean?"

The Warburg effect describes how cancer cells can metabolize large amounts of glucose rapidly by anaerobic glycolysis to derive their energy for rapid cellular growth. That is different from normal cells that derive most of their energy from aerobic metabolism.

Identify cancers that are the result of chronic inflammation.

The active immune response in chronic inflammation predisposes to cancer. Individuals who have suffered with ulcerative colitis for 10 years or more have up to a 30-fold increase in the risk of developing colon cancer. Chronic viral hepatitis caused by hepatitis B virus or hepatitis C virus infection markedly increases the risk of liver cancer. One large study found a 66% increase in risk of lung cancer among women with chronic asthma, an inflammatory disease of the airways.

Describe the major clinical manifestations of cancer.

The clinical manifestations of cancer are numerous and depend on the localization and type of tumor. Some are apparent before actual diagnosis of a malignancy. Major clinical manifestations include pain, fatigue, cachexia, anemia, leukopenia and thrombocytopenia, and infection.

"My mother had stage IV cancer and she died; I had stage I cancer and I survived," says Mr. Gillespie. "Obviously stage IV is worse, but how do they doctors determine what stage a cancer is?"

They look at the size of the tumor, how many lymph nodes it has involved, and if it has spread to distant locations in the body.

the process by which a normal cell becomes a cancer cell

Transformation

abnormal growth resulting from uncontrolled proliferation

Tumor

Which gene in its normal state negatively regulates cell proliferation?

Tumor-suppressor genes

Biologically, why do tumor-suppressor genes have to be inactivated to cause cancer?

Tumor-suppressor genes are genes whose major function is to negatively regulate cell growth and prevent mutations. Tumor suppressors normally slow the cell cycle, inhibit proliferation resulting from growth signals, or stop cell division when cells are damaged. Thus, tumor suppressors must be inactivated to allow cancer to occur and proliferate.

The process whereby tumor cells generate their own blood supply is referred to as

angiogenesis

Tumors stimulate formation of new blood vessels by secreting ___ factors.

angiogenic

Why is angiogenesis important to cancer development?

Tumors need their own blood supply to deliver oxygen and nutrients. Tiny cancers lack the ability to grow new blood vessels and may never grow larger than a grain of sand. More advanced cancers can secrete multiple factors that stimulate new blood vessel growth, angiogenesis. These angiogenic factors recruit new vascular endothelial cells and initiate the proliferation of existing blood vessel cells to allow small cancers to become large cancers. As a result of angiogenesis, normal tissue becomes deprived of perfusion, nutrients, and circulation. This results in weakening of nontumor tissue.

Distinguish between mutations in somatic cells versus in germ cells.

When genetic events occur in somatic cells, they are not transmitted to future generations. Mutations that occur in germ cells are heritable and are transmitted to future generations.

A cancerous tumor that is very poorly differentiated is referred to as being:

anaplastic

A characteristic of a malignant tumor includes that it:

can spread far from the tissue of origin

The serum marker used to evaluate a tumor of the adrenal gland is:

catecholamines

Survival of malignant tumors is facilitated by tumor-associated ___ that secrete cytokines and other factors that assist cancer cell survival and proliferation.

macrophages

Progression from a benign polyp to a malignant tumor requires (multiple, one or two) mutations.

multiple

In the presence of oxygen, normal cells metabolize glucose by (glycolysis, oxidative phosphorylation), but cancer cells often metabolize it by (glycolysis, oxidative phosphorylation).

oxidative phosphorylation; glycolysis

A mutation that occurs due to changes in nucleotide base-pairs is described as a:

point mutation

If the cancer stem cells in a tumor survive cytotoxic chemotherapy, the tumor is likely to (self-destruct, regrow).

regrow

Cancer of the connective tissue is referred to as a:

sarcoma

Cancer-predisposing genetic events that occur in ____ cells are not inherited, but those that occur in ___ cells are inherited.

somatic; germline

Stem cells and cancer cells are able to divide indefinitely because they make the enzyme ___.

telomerase

The immune system is important in protecting against cancers caused by specific ___ infections.

viral

When a patient is diagnosed with a benign tumor, it can be assumed that the tumor is: (select all that apply)

well encapsulated well differentiated.