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 Instructor: Dr. Darling-Reed, PhD

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer  Derived from Greek word for crab, karkinoma  Malignant tumor  Tumor  Also referred to as a neoplasm— new growth

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)

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 Leiomyoma Leiomyoma Chondroma Chondroma

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 tissues from which they arise Malignant epithelial tumors are referred to as carcinomas Malignant epithelial tumors are referred to as carcinomas  Adenocarcinoma Malignant connective tissue tumors are referred to as sarcomas Malignant connective tissue tumors are referred to as sarcomas  Rhabdomyosarcomas

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Classification and Nomenclature  Cancers of lymphatic tissue are lymphomas  Cancers of blood-forming cells are leukemias  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

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer Cells  Transformation  Autonomy Cancer cell’s independence from normal cellular controls Cancer cell’s independence from normal cellular controls  Anaplasia Pleomorphic- variable in size and shape Pleomorphic- variable in size and shape

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Cancer Stem Cells  Stem cells self-renew  Cell divisions create new stem cells  Stem cells are pluripotent  Ability to differentiate into multiple different cell types

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

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, in the blood, CSF, or urine  Hormones  Enzymes  Genes  Antigens  Antibodies

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:  Screen and identify individuals at high risk for cancer  Diagnose specific types of tumors  Observe clinical course of cancer

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  Clonal proliferation or expansion  As a result of a mutation, a cell acquires characteristics that allow it to have selective advantage over its neighbors Increased growth rate or decreased apoptosis Increased growth rate or decreased apoptosis  Multiple mutations are required before cancer can develop

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Mutated Genes  Secretion of growth factors (autocrine stimulation)  Increased growth factor receptors  Signal from cell-surface receptor is mutated in the “on” position  Mutation in the ras intracellular signaling protein

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Types of Mutated Genes  Inactivation of Rb tumor suppressor  Activation of protein kinases that drive the cell cycle  Mutation in the p53 gene

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

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Angiogenesis  Growth of new vessels  Advanced cancers can secrete angiogenic factors (VEGF)  Avastin (bevacizumab) is the first antiangiogenesis drug approved- monoclonal antibody that binds to and inactivates VEGF

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

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

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 and are held in place by telomerase  Telomeres become smaller and smaller with each cell division  Cancer cells- telemorase activated to lengthen telomere and protect chromosome

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Oncogenes and Tumor-Suppressor Genes  Oncogenes  Mutant genes that in their nonmutant state direct protein synthesis and cellular growth  Tumor-suppressor genes  Encode proteins that in their normal state negatively regulate proliferation  Also referred to as anti-oncogenes

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutation of Normal Genes  Point mutations  Changes in one or a few nucleotide base pairs  Chromosome translocation  A piece on one chromosome is transferred to another

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutation of Normal Genes  Chromosome amplification  Duplication of a small piece of chromosome over and over  Results in an increased expression of an oncogene

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

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutation of Normal Genes  Mutation of tumor-suppressor genes  Allows unregulated cellular growth  Loss of heterozygosity  Both chromosome copies of a gene are inactivated  Gene silencing  Whole regions of chromosomes are shut off while the same regions in other cells remain active

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

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Mutation of Normal Genes  Caretaker genes  Encode for proteins that are involved in repairing damaged DNA  Chromosome instability  Increased in malignant cells  Results in chromosome loss, loss of heterozygosity, and chromosome amplification

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Genetics and Cancer-Prone Families  Mutagen exposure  Genetic events, but NOT inherited  Mutations in tumor-suppressor genes

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Genetics and Cancer  Exposure to mutagens  If the mutation occurs in somatic cells, it is not passed to progeny  If the mutation occurs in germline cells, it can be passed to future generations

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Viruses and Cancer  Implicated  Hepatitis B and C viruses  Epstein-Barr virus (EBV)  Kaposi’s sarcoma herpesvirus (KSHV)  Human papillomavirus (HPV)  Human T cell leukemia–lymphoma virus (HTLV)

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 Peptic ulcer disease Stomach carcinoma Stomach carcinoma Mucosa-associated lymphoid tissue lymphomas Mucosa-associated lymphoid tissue lymphomas

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  Cytokine release from inflammatory cells  Free radicals  Mutation promotion  Decreased response to DNA damage

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Tumor Spread  Direct invasion of contiguous organs  Known as local spread  Metastases to distant organs  Lymphatics and blood  Metastases by way of implantation

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Phases of Tumor Spread  Transformation  Growth  Local invasion  Distant metastasis

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Local Spread  Invasion  Cellular multiplication Mitotic rate vs. cellular death rate Mitotic rate vs. cellular death rate  Mechanical pressure  Release of lytic enzymes  Decreased cell-to-cell adhesion  Increased motility Intravasation Intravasation Extravasation Extravasation

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Three-Step Theory of Invasion  Tumor cell attachment  Fibronectin and laminin  Degradation or dissolution of the matrix  Enzymes  Locomotion into the matrix  Invadopodia (pseudopodia)

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Metastasis  Spread of cancer from a primary site of origin to a distant site  Steps Direct or continuous extension Direct or continuous extension Penetration into lymphatics, blood vessels, or body cavities Penetration into lymphatics, blood vessels, or body cavities Transport into lymph or blood Transport into lymph or blood Transport to secondary sites Transport to secondary sites Entry and growth in secondary sites Entry and growth in secondary sites

Elsevier items and derived items © 2008 by Mosby, Inc., an affiliate of Elsevier Inc. Some material was previously published. Distant Metastases  Metastasis often occurs in the first capillary bed encountered by circulating cells  Organ tropism  Preferential growth of cancerous cells in certain organs Growth factors, chemokines, hormones, tissue-selective homing receptors, and chemotactic factors Growth factors, chemokines, hormones, tissue-selective homing receptors, and chemotactic factors