Published on January 22, 2008
Slide1: Donald Vander Griend Ph.D. Huggins Lecture Series February 19, 2005 QUESTIONS? Email me at [email protected] Access these lectures on the web: http://ben-may.bsd.uchicago.edu then click on “Presentations” Lecture Outline: Lecture Outline Jan 15 - The Problem, The Prostate, and The Man Jan 22 - What is Cancer? Jan 29 - The Causes of Prostate Cancer Feb 5 - Diagnosing Prostate Cancer Feb 12 - Treating Prostate Cancer TODAY - Prostate Cancer Metastasis Feb 26 - Hormones and Prostate Cancer March 5 - Emerging and Novel Treatment Techniques - Hope for the Future If You Recall…Lecture 5Treating Prostate Cancer: If You Recall…Lecture 5 Treating Prostate Cancer Early Disease Retropubic or Perineal Radical Prostatectomy External-Beam and Brachytherapy Cryotherapy Watchful Waiting Complications associated with Continence and Potency Advanced Disease Hormone Therapy Chemotherapy Pain Management of Metastases Prostate Cancer Metastasis: Prostate Cancer Metastasis What is Metastasis? Organ Specificity of Metastasis Biology of Bone and Bone Turnover Prostate Cancer Bone Metastases Studying Bone Metastases Tumors Rarely Kill Patients: Tumors Rarely Kill Patients Tumor cells are rarely lethal unless they form a mass in a vital organ (i.e. brain). Tumor cells can become lethal when they invade the surrounding tissue and spread to other organs (a.k.a. malignancy). This process is termed “metastasis”, where tumor cells travel to other organs and form tumors within that organ. What Is Metastasis?: What Is Metastasis? Meta = change; stasis = state The process whereby a tumor cell: Invades and leaves the original tumor Transports to another organ Divides out of control within that organ. Metastases are secondary tumors that are disjointed from the original (primary) tumor. Diagram of Metastasis: Diagram of Metastasis Development of overt metastases Primary Tumor Metastasis Tumorigenesis Clinically Significant Secondary Tumors Why is Metastasis Bad?: Why is Metastasis Bad? Once a tumor metastasizes, it is difficult to cure by surgery or radiation. Metastatic cancer cells forming tumors in other organs can impede the function of that organ. Growing metastases may destroy the organ they inhabit. Prostate bone metastases: change bone structure and bone marrow function. Cause pain, blood production, and skeletal problems. Metastasis is Organ Specific: Metastasis is Organ Specific It has long been observed that certain cancers prefer certain organ sites of metastasis. Cancer Preferred Metastatic Site(s) Prostate Breast Colon Lung Bone Bone (liver, brain, lung) Liver Brain The Debate of Organ Specificity I: The Debate of Organ Specificity I ENVIRONMENTAL 1889: Stephen Paget’s Seed and Soil Hypothesis. The “seed” (cancer cell) will grow only if it falls on congenial “soil” (factors in the organ environment). Certain organs are better for certain cancer cells. The Debate of Organ Specificity II: The Debate of Organ Specificity II ANATOMICAL 1920’s: James Ewing challenged that it’s the anatomic circulatory patters between the tumor and the metastatic site. Functions of Bone: Functions of Bone Structural Locomotion Protection of internal organs Metabolic Storehouse for Calcium and Phosphorous Regulate body pH Protects by binding toxins and heavy metals Hematopoietic (Blood) Marrow is region where many blood cells are made Bone Composition: Bone Composition Bone tissue consists of: Bone cells: Osteoblasts – form bone Osteoclasts – break down bone Collagen fibrils arranged in an orderly matrix. Calcium and phosphate mineral deposits (hydroxyapatite) Collagen Fibril Three interwoven protein strands Type I (also found in skin) Many fibrils are linked together to form matrix Bone Anatomy: Bone Anatomy Trabecular Bone Less dense and spongy. More metabolically and hematopoietically active. Ends of long bones, vertebrae, flat bones. Cortical Bone Dense and Compact. Major function is to provide strength and protection. Long bones. Bone Turnover: Bone Turnover The skeleton is metabolically active and constantly remodeling. Highly-regulated process. Precise balance between bone break-down (osteoclasts) and bone formation (osteoblasts). Osteoclast Large, multi-nucleated. Resorbs bone by dissolving minerals and degrading collagen. Osteoblast Forms bone by producing collagen and promoting mineralization. Resorption Formation Diseases of Bone Turnover: Diseases of Bone Turnover Resorption Formation Healthy Balance Resorption = Formation Resorption Formation Resorption > Formation Resorption Formation Resorption < Formation OSTEOPOROSIS (Abnormal Bone Destruction) OSTEOSCLEROSIS (Abnormal Bone Formation) Bone Marrow: Bone Marrow Soft material within bones. Yellow Marrow: Contained within long, compact bone. Consists mostly of fat and contains very few cells. Red Marrow: Contained within spongy, trabecular bone. Consists of hematopoietic stem cells which give rise to red blood cells, white blood cells, and platelets. VERY rich and active growth environment. ? Bone Metastases: Bone Metastases Prostate and Breast tumors are particularly prone to develop bone metastases (85% of patients have evidence of bone metastases at autopsy). Thyroid, lung, and kidney cancers also commonly spread to bone (30-40% have evidence at autopsy). Gastric cancers rarely metastasize to bone (5% have evidence at autopsy). Prostate Cancer Bone Metastases(Predominant Sites): Prostate Cancer Bone Metastases (Predominant Sites) Femur Pelvis Lumbar Spine Dorsal Spine Less Common: Ribs, Skull, & Clavicle Most Common: Spine, Pelvis, Femur Ribs Clavicle Skull Two Patients With Prostate Cancer Bone Metastases: Two Patients With Prostate Cancer Bone Metastases Metastases Metastases Bone Scan Prostate Cancer Bone Metastases Under a Microscope: Prostate Cancer Bone Metastases Under a Microscope Bone Tissue Prostate Cancer Cells From: Roudier et al. Hum Path. 34: 646, 20003. Prostate Cancer Bone Metastases: Prostate Cancer Bone Metastases ~ 65% of prostate bone metastases induce the abnormal formation of bone (osteoblastic). ~ 12% of prostate bone metastases are bone destroying (osteolytic). ~ 23% are appear to have a mixed osteoblastic/osteolytic appearance (high activity, no significant change in bone mass). Osteoblastic Bone Metastases: Osteoblastic Bone Metastases A metastatic prostate cancer cell is interacting and affecting the bone environment. Question: How does it do that? Bigger Question: What can be done to stop it? Prostate Cancer Cell and Osteoblast Interaction: Prostate Cancer Cell and Osteoblast Interaction Clinical Manifestations of Bone Metastases: Clinical Manifestations of Bone Metastases Pain Spinal cord compression and paralysis Weakness of bones leading to fractures (osteolytic) Changes in serum calcium and phosphate levels Bone marrow failure Anemia (deficient red blood cells) Leukopenia (deficient white blood cells) Thrombocytopenia (deficient platelets) Treating Prostate Cancer Bone Metastases: Treating Prostate Cancer Bone Metastases Detection by bone scan. Radiation of painful sites. Rarely, surgery for fractures or spinal cord compression can be done. Bisphosphonates: attempt to slow down bone metabolism and prevent skeletal complications of bone metastases. Analgesics for pain. Hormone ablation (till progression to Hormone-Refractory Prostate Cancer – HRPC) Why Does Prostate Cancer Metastasize to Bone?: Why Does Prostate Cancer Metastasize to Bone? Ewing: it goes to bone because the blood flow from the prostate goes there (Anatomic). Paget: it goes to bone because the bone is a favorable environment for prostate cancer cells (Seed and Soil). Detecting Prostate Cancer Cells in Blood and Bone Marrow: Detecting Prostate Cancer Cells in Blood and Bone Marrow Purpose: use a highly-sensitive technique to detect prostate cancer cells in patient bone marrow or blood. How? A technique called Polymerase Chain Reaction (PCR) is used to detect expression of Prostate-Specific Antigen. How sensitive? 1 prostate cell among 1 million normal blood cells. Prostate Cancer Cell Dissemination is Early and Widespread: Prostate Cancer Cell Dissemination is Early and Widespread PSA-expressing cells can be detected in the circulation and bone marrow even when the tumor is confined to the prostate (T1 or T2). Many different studies by numerous investigators. The presence of cells in blood or bone marrow does NOT predict the development of metastases. In fact, many patients in these studies never developed clinically significant metastases. Dissemination ≠ Metastasis: Development of overt metastases Primary Tumor Metastasis Tumorigenesis Blocked at this Stage Dissemination ≠ Metastasis Why Does Prostate Cancer Metastasize to Bone?: Why Does Prostate Cancer Metastasize to Bone? Ewing (Anatomic) vs. Paget (Seed and Soil) Current data convincingly shows that prostate cancer cells disseminate widely throughout the body. However, these disseminated cells seem to form metastases only in the bone environment. The “seeds” are scattered everywhere, but prefer to grow in the bone environment (“soil”). ? Studying Bone Metastasis: Studying Bone Metastasis Animal models of bone metastasis. Evaluating human prostate cancer bone metastases. Modeling Prostate Cancer Bone Metastasis in an Animal: Modeling Prostate Cancer Bone Metastasis in an Animal Purpose: To understand what prostate cancer cells do in the bone environment. What can be done to stop them from growing and affecting bone function. One Approach: Implant human bone onto a mouse and inject prostate cancer cells into it. Inject Prostate Cancer Cells Studying Human Prostate Cancer Metastases: Studying Human Prostate Cancer Metastases Obtaining and analyzing tissues from human prostate cancer bone metastases is an ideal approach to understanding bone metastases. Problem: bone metastases are rarely removed surgically during treatment. Consequence: short supply of high-quality tissue for scientists to study. Rapid (“Warm”) Autopsies: Rapid (“Warm”) Autopsies Tumor donor program that allows men with advanced and metastatic prostate cancer to consent to an immediate autopsy shortly after death. Multi-disciplinary team on a round-the-clock basis at approved institutions. Procure metastatic and normal tissue. Tissue is either preserved for analysis or implanted into a mouse and grown (xenograft). Represents a valuable resource for prostate cancer researchers. Rapid Autopsies: Initial Findings: Rapid Autopsies: Initial Findings Initially enrolled patients with hormone-refractory prostate cancer (HRPC). At most metastatic sites, the tumor had completely replaced the bone marrow. Wide variety of tissue patterns, some metastases still had glandular patterns. Wide range of PSA expression – some metastases had none, others had mixture of PSA-positive and PSA-negative cells. Patients also had smaller yet significant metastases in the liver, lymph nodes, lungs, dura, and adrenal glands. Rapid Autopsy Tissues: The Future: Rapid Autopsy Tissues: The Future High-quality tissue of human prostate cancer bone metastases. Also possess matching normal tissue and, when possible, the original prostate tumor. Living metastatic tumor tissue is being propagated in mice (xenograft). Powerful tool for molecular and genetic analyses to identify genes and factors that may be important in prostate cancer. My Research: Metastasis Suppressor Genes: My Research: Metastasis Suppressor Genes Oncogenes: genes whose protein product functions to promote cell division and promote tumorigenesis. Tumor Suppressor Genes: genes whose protein product functions to block cell division and the formation of a tumor. Metastasis Suppressor Genes (MSGs): genes whose protein product functions to block the metastatic ability of a tumor cell. Metastasis Suppressor Genes: Tumorigenesis Metastasis Suppressor Genes Oncogenes and Tumor Suppressor Genes Metastasis Suppressor Genes: Utilities: Metastasis Suppressor Genes: Utilities Identify genes whose expression can aid in predicting disease behavior (metastasis markers). Increase our understanding of the complicated process of metastasis. Identify genes that serve important functions in metastasis in order to develop effective anti-metastatic therapies. ? Sources: Sources The Biology of Skeletal Metastasis. Edited by Keller and Chung. Kluwer Academic Publishers, 2004. Shah et al. Androgen-Independent Prostate Cancer is a Heterogenous Group of Diseases: Lessons from a Rapid Autopsy Program. Cancer Research, 64: 9209, 2004. Corey and Corey. Detection of disseminated prostate cells by reverse transcription-polymerase chain reaction (RT-PCR): technical and clinical aspects. Int J Cancer 77:655-73, 1998. Sartor and Steven. Management of bone metastases in advanced prostate cancer. UpToDate.com, 2004. Raisz. Normal skeletal development and regulation of bone formation and resorption. UpToDate.com, 2004.