1. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Biology of Cancer and Tumor Spread Chapter 9

2. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer Characteristics  Neoplasm – new growth, involves the overgrowth of tissue to form a neoplastic mass (tumor).  Benign – growth is relatively slow and orderly, and tumor remains localized.  Malignant – characterized by rapid, disorderly growth and aggressive invasion into adjacent normal tissue.  May metastasize to another part of the body (benign tumors, by definition, never do this).

3. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Benign vs. Malignant Tumors BenignMalignant Grow slowly Grow rapidly Well-defined capsule Not encapsulated Not invasive Invasive Well differentiated Poorly differentiated Low mitotic index High mitotic index Do not metastasize Can spread distantly (metastasis)

4. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cell Differentiation  Transformation – process of a normal cell becoming a cancer cell.  Cancer cells exhibit autonomy and anaplasia.  Autonomy –cancer cell is independent from normal cellular controls.  Anaplasia – loss of differentiation; cancer cell reverts to a less mature form.

5. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cell Differentiation  Differentiation – process by which a cell develops specialized functions, organization and other more mature characteristics.  Cancer cells often de-differentiate.  Pleomorphic – anaplastic cells have a variable size and shape (normal cells are more uniform)

6. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

7. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification and Nomenclature  Benign tumors  Named according to the tissues from which they arise, and include the suffix “-oma” Lipoma Lipoma Glioma Glioma Chondroma Chondroma

8. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification and Nomenclature  Malignant tumors - named according to the cell type from which they originate.  Carcinomas - malignant epithelial tumors Adenocarcinomas - malignant glandular tumors Adenocarcinomas - malignant glandular tumors  Sarcomas - malignant connective tissue tumors

9. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification and Nomenclature  Lymphomas - cancers of lymphatic tissue  Leukemias - cancers of blood-forming cells  Carcinoma in situ (CIS)  Preinvasive epithelial malignant tumors of glandular or epithelial origin that have not broken through the basement membrane or invaded the surrounding stroma

10. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

11. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. ACTIVITY 1. Abnormal, proliferating cells possessing a higher degree of autonomy than normal cells. 1. Abnormal, proliferating cells possessing a higher degree of autonomy than normal cells. 2. Lack of cellular differentiation or specialization; primitive cells. 2. Lack of cellular differentiation or specialization; primitive cells. 3. Slow growing mass of cells that remains at the original site. 3. Slow growing mass of cells that remains at the original site. 4. Cancer cells’ independence from normal cellular controls. 4. Cancer cells’ independence from normal cellular controls.

12. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification by Histology and Genetics  Histological examination of biopsied tissue is used to diagnose and classify tumors.  Immunohistochemical analysis of genetic alterations is used to analyze protein expression  Genetic testing is done to identify specific mutations.

13. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification by Histology and Genetics  Example – breast cancer is typed according to:  Hormone receptor status (estrogen and/or progesterone positive or negative)  Growth factor receptor status (HER2 positive or negative)  Allows for improved treatment since different types respond to different treatments.

14. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor Markers  Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on plasma cell membranes or in the blood, CSF, or urine.  Examples – hormones, enzymes, genes, antigens or antibodies.

15. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor Markers  Hormones may be over-secreted by tumors of glandular tissue (as in pheochromocytoma, a cancer of the adrenal medulla which over-secretes adrenaline).  Alpha-fetoprotein (AFP) is secreted by liver and germ cell tumors.  Prostate-specific antigen (PSA) is secreted by prostatic carcinoma.

16. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor Markers  Tumor markers are used to: 1. Screen and identify individuals at high risk for cancer 2. Diagnose specific types of tumors 3. Observe clinical course of cancer

17. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Genetic Basis of Cancer  Cancer involves the transformation of normal cells into cells that exhibit:  Decreased need for growth factors to multiply  Lack of contact inhibition  Anchorage independence  Immortality

18. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer-Causing Mutations  Cancer is predominantly a disease of aging.  As we age our cells accumulate mutations, some of which may lead to cancer.

19. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

20. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer-Causing Mutations  Clonal proliferation or expansion –  As a result of a mutation, a cell may acquire characteristics that allow it to have selective advantage over its non-mutant neighbor cells.  Increased growth rate or decreased apoptosis.  This gives rise to an early stage tumor.  Multiple mutations are required before cancer can develop.

21. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

22. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Oncogenes and Tumor-Suppressor Genes  Proto-oncogenes – normal genes that direct protein synthesis and cellular growth.  Oncogenes – form when the genes above are mutated so that they are no longer under normal control; cause increased cell division.  Tumor-suppressor genes - encode proteins that in their normal state negatively regulate proliferation. Also referred to as anti-oncogenes.

23. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutations that Create Oncogenes  Point mutations –  Changes in one or a few nucleotide base pairs that release a gene from regulation.  Most common way that oncogenes form.  Example: ras gene.

24. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutations that Create Oncogenes  Chromosome translocation – a piece on one chromosome is transferred to another where either:  The oncogene is overexpressed myc gene in Burkitt’s lymphoma myc gene in Burkitt’s lymphoma  A new protein is made that acts as an oncogene BRC-ABL fusion in chronic myeloid leukemia BRC-ABL fusion in chronic myeloid leukemia

25. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Chromosome Translocation

26. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutations that Create Oncogenes  Gene amplification  Duplication of a small piece of chromosome over and over.  Results in an increased expression of an oncogene. N-myc in neuroblastomas N-myc in neuroblastomas erbB2 in breast cancer erbB2 in breast cancer

27. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

28. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Amplification of N-myc in Neuroblastoma

29. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor-suppressor Genes  Normal functions –  Slow cell cycle  Inhibit proliferation from growth signals  Stop cell division when cells are damaged.  Examples –  Rb (retinoblastoma) gene normally strongly inhibits the cell division cycle.  p53 induces apoptosis in damaged cells.

30. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor-suppressor Genes  Mutation of tumor-suppressor genes  Allows unregulated cellular growth  However, both copies of the gene must be inactivated before the cell is released from inhibition.

31. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Loss of Heterozygosity  The first mutation is often a point mutation in one allele.  The second mutation is often loss of an entire region of the homologous chromosome that contains the normal tumor suppressor gene. This unmasks the point mutation.  Loss of heterozygosity – loss of a chromosome region in a tumor (this is where the normal, heterozygous copy was located).

32. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Loss of Heterozygosity

33. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Epigenetic Gene Silencing  Whole regions of chromosomes are shut off while the same regions in other cells remain active.  Occurs on one member of a pair of homologous chromosomes.  This is a normal cellular process that occurs by methylation of DNA.  In cancer cells, silenced regions sometimes spread to turn off tumor suppressor genes.  This can also unmask point mutations on the other chromosome.

34. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Gene Silencing

35. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Chromosome Instability  Chromosome instability  Increased in cancer cells  Results in: Higher rate of chromosome loss Higher rate of chromosome loss Loss of heterozygosity Loss of heterozygosity Chromosome amplification Chromosome amplification

36. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. ACTIVITY 1. Why is it necessary for BOTH copies of a tumor suppressor gene to be knocked out in cancer cells? 2. What is the difference between loss of heterozygosity and gene silencing?

37. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Genetics of Cancer  Genetics of cancer – usually caused by genetic mutations in somatic cells during the lifetime of the individual. Thus they are genetic events, but NOT inherited.  Mutagen exposure – can increase a person’s risk of developing mutations.

38. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer-Prone Families  If the mutation occurs in germline cells, it can be passed to future generations.  Predispose offspring to a specific form of cancer.  Such mutations are in tumor-suppressor genes and caretaker genes.

39. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Gene Mutations in Cancer Alteration of progrowth signals  Autocrine stimulation – cancer cells gain the ability to secrete their own growth factors.  Increased growth factor receptors – so they respond more to normal levels of growth factor.

40. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Gene Mutations in Cancer Alteration of progrowth signals  Signal from cell-surface receptor is mutated in the “on” position – so cell is signaled to divide even in the absence of growth factors.  Example - mutation in the ras intracellular signaling protein

41. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Mutated Genes

42. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Gene Mutations in Cancer Alteration of antigrowth signals  Inactivation of Rb tumor suppressor (normal Rb gene inhibits cell growth).  Activation of protein kinases that drive the cell cycle.  Mutation in the p53 gene causes a cell to avoid apoptosis (they no longer undergo programmed cell death when there is excess growth like a normal cell would).

43. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Gene Mutations in Cancer  Mutations that allow metastasis  Decreased cell-to-cell adhesion  Secretion of proteases that digest surrounding barriers  Ability to grow in new locations

44. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Mutated Genes

45. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Angiogenesis  As tumors grow in size they need their own blood supply to deliver oxygen and nutrients to support their rapid mitosis.  Angiogenesis it the process of new blood vessel formation.  Advanced cancers can secrete angiogenic factors (like VEGF) that stimulate formation of vessels in the area around them.  Avastin (an anticancer drug) is a monoclonal antibody that inactivates VEGF.

46. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Angiogenesis

47. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Telomeres and Immortality  Body cells are not immortal and can only divide a limited number of times.  Telomeres are protective caps on each chromosome which become smaller and smaller with each cell division.

48. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Telomeres and Immortality  Telomeres are maintained germ cells and stem cells (which are immortal) by the enzyme telomerase.  Cancer cells are able to produce telomerase, which allows their chromosomes to divide an unlimited number of times.

49. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Telomeres and Immortality

50. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Hallmarks of Cancer

51. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Inflammation and Cancer  Chronic inflammation is an important factor in the development of cancer.  Examples –  Liver cancer (HBV and HCV infections)  Colon cancer in people with ulcerative colitis  Lung cancer in people with chronic asthma.

52. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Inflammation and Cancer  Inflammation is associated with cancer through a number of processes:  Cytokine and growth factor release from inflammatory cells – stimulates local cell proliferation  Free radicals released by inflammatory cells – cause DNA damage and mutations.  Angiogenesis is stimulated by inflammatory cells and interleukins.

53. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published.

54. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Inflammation and Cancer  Inflammation increases in the enzyme which generates prostaglandins (COX-2) are associated with colon cancer and others.  NSAIDs (which inhibit COX-2) protect against development of colon cancer.

55. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Immune System and Cancer  Healthy immune system protects against viral-associated cancer.  Immunosuppression fosters cancer  Non-Hodgkin lymphoma (10X) - EBV  Kaposi sarcoma (1000X) – HHV8  In some cases cancer promotes secretion of cytokines that foster cancer.  At the same time, other immune system cells exert antitumor effects.

56. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Viral Causes of Cancer  Implicated in about 15% of human cancers worldwide.  Hepatitis B and C viruses (HBV and HCV)  Chronic infections cause chronic liver inflammation  Contributes to about 80% of all cases of hepatocellular carcinoma.

57. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Viral Causes of Cancer  Human papillomavirus (HPV)  Infects basal skin cells and causes warts.  Some subtypes are associated with cervical, anogenital, and penile cancer.  HPV inserts into chromosomes where it can cause overexpression of oncogenes.  Vaccines are now available to HPV (Gardasil and Cervarix) which prevent infection and subsequent cancer.

58. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Viral Causes of Cancer  Epstein-Barr virus (EBV)  Acute infection causes infectious mononucleosis.  Persistent infections can result in B cell lymphomas, especially in immunosuppressed individuals.  Kaposi’s sarcoma herpesvirus (KSHV = HHV8) –  Associated with Kaposi’s sarcoma in elderly males and immunocompromised individuals.

59. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Viral Causes of Cancer  Human T cell leukemia–lymphoma virus (HTLV)  Retrovirus that is linked to development of adult T cell leukemia and lymphoma.  Inserts into DNA and can be inherited by offspring or passed to others through breastfeeding and other body fluids.  Only a very small percentage of individuals infected with these viruses actually develop the related cancers.

60. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Bacterial Cause of Cancer  Helicobacter pylori – chronic infections are associated with:  Peptic ulcer disease  Stomach carcinoma  Mucosa-associated lymphoid tissue lymphomas in gastric wall  H. pylori infections can be treated with antibiotics, which often results in regression of lymphomas.

61. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer Progression and Metastasis  Metastasis – the spread of cancer cells from the site of the original tumor to distant tissues and organs throughout the body.  Metastasis is a defining characteristic of malignancy.

62. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Local Spread  First step in the progression of cancer.  Several mechanisms facilitate the local spread of cancer. These include:  Cellular proliferation  Angiogenesis  Release of lytic enzymes causes tissue degradation and digestion of barriers  Decreased cell-to-cell adhesion  Increased motility of tumor cells

63. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Local Spread  The size of tumors increases when the rate of cellular proliferation exceeds the rate of cell death.  As the tumor grows, it exerts mechanical pressure on surrounding tissues.  As this pressure increases, the tumor sends projections into the surrounding tissue.

64. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Local Spread  The multiple projections arising from the central tumor mass give it a crab-like appearance, which gave rise to the term cancer.  Pressure on nearby blood vessels can lead to local tissue ischemia, making it easier for the tumor to expand into these tissues.

65. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Patterns of Spread Two distinct mechanisms give rise to patterns of metastatic spread. 1. Cancer cells spread through lymphatic vessels (most common route) and blood vessels (usually veins), as well as natural tissue planes.  Clusters, single cells, and fragments of tumor can disseminate by these routes.

66. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Sequential Process of Metastasis

67. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Patterns of Spread 2. Organ tropism - different cancers selectively metastasize to different sites.  Breast cancer often spreads through the bloodstream to bones but rarely to kidney or spleen.  Lymphomas often spread to the spleen but uncommonly spread to bone.  Selectivity is likely due to specific interactions between the cancer cells and specific receptors on the small blood vessels in different organs.

68. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Patterns of Spread  Cancer cells that travel through veins from most parts of the body commonly metastasize to the lungs.  Cancer cells that arise in the abdomen commonly metastasize to the liver.

69. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. ACTIVITY 1. Explain, in terms of patterns of venous blood flow, why cancers from most parts of the body tend to metastasize to the lungs. 2. Explain why cancers from the abdominal organs tend to metastasize to the liver.

70. Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Stages of Cancer Spread  Four stage system - categorizes solid malignant tumors for their invasion and metastasis potential.  Stage I – cancer is restricted to its organ of origin.  Stage II – cancer is locally invasive.  Stage III – cancer has spread to regional structures such as lymph nodes.  Stage IV – cancer has spread to distant sites.  Cancers caught in earlier stages generally have a better prognosis.