N715 Exam 3 Part 5 PDF

○ At the G1/S checkpoint, there is a gatekeeper of the checkpoint called the TP53 gene, which will not work properly if mutated ○ Once the cell makes it past that growth cycle, it will continue to acquire additional mutations along the way Normal cells vs can...

○ At the G1/S checkpoint, there is a gatekeeper of the checkpoint called the TP53 gene, which will not work properly if mutated ○ Once the cell makes it past that growth cycle, it will continue to acquire additional mutations along the way Normal cells vs cancer cells ○ Normal Stop growing when enough cells are present, repair themselves or die in cell cycle, do not spread When removed, don’t grow back May cause compression of nearby tissues but usually only problem in closed spaces (ie brain) Highly organized, multiple checkpoints that direct entry into and out of cell cycle phases Intrinsic and extrinsic induced apoptosis ○ cancer Continue to grow after enough cells are present, ignore signals to stop or die Spread or invade nearby and distant tissues May grow back or recur if removed Uncontrolled growth can cause tissue stiffness and compression Uncontrolled cell growth, continuous proliferation Suppressed apoptosis which lead to prolonged cell life Cancer cells have 6 main characteristics ** self-sufficiency in growth signals, ○ Typically, cells of the body require hormones and other molecules that act as signals for them to grow and divide. ○ Cancer cells have the ability to grow without these external signals ○ Several ways of doing this: 1) Autocrine signaling – they make their own signals which increase their ability to grow and survive 2) Destroying tumor suppressor genes which are the “off switches” ie TP53 ○ Leads to chaotic, unmanaged replication, cell division and growth ** insensitivity to antigrowth signals ○ When tumors cells get too big, they make contact with other cells The contact triggers signals that are meant to prevent the cell from growing any bigger or dividing. ○ In cancer cells, the signals are not effective and the cell keeps growing and dividing. ○ A fast growing tumor almost always creates a hypoxic environment due to several interconnected reasons including unsynchronized growth rates of tumor cells and endothelial cells, disorganized vascular architecture, sluggish blood flow and high interstitial fluid pressure. ** immortality (evading apoptosis) ** sustained angiogenesis, ○ Tumors have limited supply of oxygen -> causes areas of necrosis Results in need for glucose uptake and glycolysis tp generate energy -> results in lactate production Causes tumors to light up on PET scans ○ Need to develop a circulatory system to live ○ - Solid tumors secrete a growth factor called Vascular Endothelial Growth Factor [VEGF] which helps tumor cells grow their own oxygen supply.  ** tissue invasion and metastasis ○ Cancer cells can break away from their site of origin to invade and spread to distant sites ○ Property unique to cancer cells ○ Multi-step process including blood vessel invasion, spread through the circulatory system, and deposition/ growth in new tissues Limitless replicative potential ○ Cell normally decreases in size/ shortens by regulates # of divisions ○ Tumor cells secrete an enzyme called telomerase , which prevents destruction of the telomere ** About 85% of cancers upregulate telomerase – which extends their telomeres Carcinogens ○ Substances that cause cancer. ○ - The process of cancer development is called carcinogenesis. ○ Certain chemicals ○ - Asbestos, nickel, cadmium, radon, vinyl chloride, benzidene, and benzene. ○ One of the most potent in humans is benzo[a]pyrene found in cigarette smoke. ○ Viruses and Bacteria ○ - Some are associated with the initiation and promotion of tumor growth. ○ - Can cause cancer directly by affecting cell division, by causing chronic inflammation, or by reducing immune system function. Cancer classification ○ Cancers are classified in two ways: ○ 1) by the type of tissue in which the cancer originates (histological type), or ○ 2) by primary site, the location in the body where the cancer first developed. ○ From a histological standpoint there are hundreds of different cancers, which are grouped into six major categories: 1) Carcinoma malignant cancers of epithelial origin [internal or external lining of the body 2) Sarcoma originates in the supportive and connective tissues [bone, tendons, cartilage, muscle, fat 3) Myeloma originates in the plasma cells 4) Lymphoma cancer of the lymphatic system [glands or nodes] 5) Leukemia blood cancer of the WBCs 6) Mixed types 2 or more features of different types of CA, ie carcinosarcoma [mixed epithelial cell and sarcoma cell cancers]; generally makes them incredibly aggressive cancers Cancer in Children Types of childhood cancer  ○ Blood cells start as stem cells in the bone marrow dysfunction can occur with myeloblast or lymphoblast LEUKEMIAS ○ Acute lymphoblastic leukemia CAN OCCUR IN THREE DIFFERENT AREAS OF THE BODY BLOOD/BONE MARROW SPINAL FLUID TESTES TREATMENT IS MOSTLY OUTPATIENT AND LASTS FOR TWO YEARS FOR GIRLS AND THREE YEARS FOR BOYS ○ Myeloid leukemias Acute myelogenous leukemia Most common of the myeloid disorders in children TREATMENT IS MOSTLY INPATIENT, VERY INTENSE, AND LASTS FOR 6-7 MONTHS HIGHER RATES OF RELAPSE THAN ALL WITH RELAPSE, LIKELY TO GET A BONE MARROW TRANSPLANT Chronic myelogenous leukemia SECOND MOST COMMON GENERALLY HAS SPECIFIC GENETIC MARKERS  ○ PHILADELPHIA CHROMOSOME T(9:22) - CALLED BCR/ABL ○ MAY BE TREATED WITH ORAL THERAPY IF TAKEN CORRECTLY – GLEEVEC – TARGETED THERAPY ○ IF NOT, MAY NEED BONE MARROW TRANSPLANT Myelodysplastic syndrome ○ CAN MORPH INTO AML ○ TREATMENT IS BONE MARROW TRANSPLANT BEFORE THIS HAPPENS, AS IT IS VERY HARD TO TREAT ONCE IT HAS BECOME AML ○ Juvenile myelogenous leukemia LYMPHOMAS ○ Two types Hodgkins VERY SIMILAR TO THE ADULT FORM OF HODGKIN'S LYMPHOMA. THERE ARE PEAKS IN CHILDHOOD AND AGAIN IN YOUNG ADULTHOOD 90-95% CURABLE MAY BE COMPLETELY ASYMPTOMATIC AND ONLY HAVE LYMPH NODE INVOLVEMENT ○ SUPRACLAVICULAR ○ CERVICAL MAY HAVE “B” SYMPTOMS INCLUDING UNEXPLAINED WEIGHT LOSS, NIGHT SWEATS, FEVER. PRESENCE OF THESE ARE TAKEN INTO ACCOUNT WHEN PLANNING FOR TREATMENT Non-hodgkins Includes b and t cell lymphomas  TYPE OF TREATMENT DEPENDS LARGELY ON CELLS, SITE OF DISEASE, INCLUDING INVOLVEMENT OF BONE MARROW CAN ALSO BE VERY SIMILAR TO LEUKEMIA TREATMENT BRAIN TUMORS ○ TREATMENT LARGELY DEPENDS ON LOCATION, SIZE, AND HISTOLOGY (MAKE UP) ○ INCLUDES : ASTROCYTOMAS, GLIOMAS, AT/RT, EMBRYONAL, GERM CELL, EPENDYMOMA ○ AGE OF PATIENT DOES PLAY A ROLE AS WELL- don’t give radiation treatment to those under 3- do bone marrow transplant instead OTHER SOLID TUMORS Treatment of cancer ○ CHEMOTHERAPY FIRST THING TO KNOW : IT ISN’T THAT INTELLIGENT TARGETS SPECIFICALLY CELLS THAT GROW QUICKLY WHY DO WE USE MULTIPLE AGENTS INSTEAD OF JUST ONE?- affects multiple cells at different parts of cell cycle Examples of toxicities from chemo CYCLOPHOSPHAMIDE/IFOSPHAMIDE ○ BLADDER TOXICITIES/FERTILITY ISSUES CARBOPLATIN/CISPLATIN ○ KIDNEY DAMAGE/HEARING DAMAGE ETOPOSIDE/TOPOTECAN ○ Secondary malignancies BLEOMYCIN, DACTINOMYCIN/DOXORUBICIN ○ Heart muscle issues METHOTREXATE/5 FU ○ kidney/liver issues VINCRISTINE/VINBLASTINE/VINORELBINE ○ Peripheral nerve issues ○ RADIATION USE IS DEPENDENT ON WHAT TYPE OF CANCER AND LOCATION OF THERAPY NECESSARY WORKS BY DISRUPTING DNA TO PREVENT REPLICATION OR TO KILL CELL DIRECTLY CAN BE PRIMARY THERAPY OR SECONDARY (RELAPSED) THERAPY PRIMARY – BRAIN TUMORS, SOME HODGKIN'S, NEUROBLASTOMA SECONDARY – CNS BOOST FOR ALL RELAPSE TO CNS, Total Body Irradiation FOR ALL FOR Bone Marrow Transplant SEVERAL TYPES CAN BE EXTERNAL OR INTERNAL (PLACED DURING SURGERY) DOSING IS VERY SPECIFIC Toxicities of radiation GENERALLY DEPENDS ON WHERE PATIENT HAD RADIATION THERAPY COGNITIVE EFFECTS FERTILITY ISSUES GROWTH/ENDOCRINE ISSUES SECONDARY MALIGNANCIES ○ BONE MARROW TRANSPLANT WHEN WOULD YOU DO A BONE MARROW TRANSPLANT? RELAPSE (OR MULTIPLE RELAPSES) OF CERTAIN DISEASES BAD CYTOGENETICS OR RECURRENCE/DISEASE PROGRESSION WHILE ON TREATMENT (PH + ALL, NOT GOING INTO REMISSION DURING INDUCTION CHEMO) AS PRIMARY TREATMENT (BRAIN TUMORS/NEUROBLASTOMA)  ILLNESSES WHERE THE BONE MARROW IS THE PROBLEM (IMMUNODEFICIENCIES/SICKLE CELL) WHEN YOU HAVE A BAD DISEASE AND A GOOD MATCH Note: requires re-immunization Autologous vs allogeneic AUTOLOGOUS- get cells from yourself ○ NEED TO GET BIG DOSES OF CHEMOTHERAPY IN THAT MIGHT HARM MARROW ○ BUILT IN THERAPY FOR STAGE IV NEUROBLASTOMA AND BRAIN TUMORS ALLOGENEIC- get cells from someone else, factory making wrong parts- then you start making what healthy donor makes including DNA ○ WHEN THE FACTORY IS THE PROBLEM ○ RELAPSED LEUKEMIA ○ IMMUNODEFICIENCY ○ SICKLE CELL ○ DBA ○ HLH Sources of stem cells for BMT Bone marrow PERIPHERAL BLOOD STEM CELLS- for autologous transplant CORD BLOOD ○ TARGETED MONOCLONAL ANTIBODY THERAPY ○ CAR-T CELL THERAPY CHIMERIC ANTIGEN RECEPTOR MODIFIED T CELLS RELATIVELY NEW TREATMENT FOR RELAPSED DISEASES  MAY BE USED IN COMBINATION WITH STEM CELL TRANSPLANTATION TO GET PATIENTS INTO REMISSION Lymphoma Lymphoma is defined as a type of blood cancer that effects the lymphatic system → Overview of Lymphatic System: The lymphatic system is an open, one-way network running alongside blood vessels Its main functions include Draining excess fluid from tissues Filtering out pathogens Initiating adaptive immune responses Lymphatic fluid, or lymph, originates from plasma that leaks out of blood capillaries due to pressure differences Lymph is filtered through lymph nodes, which capture and destroy pathogens and abnormal cells After filtration, lymph re-enters the bloodstream and becomes part of the blood plasma → Structure and Function of Lymphatic Capillaries Structure ○ Lymphatic capillaries are lined with specialized, highly permeable endothelial cells. ○ This design allows for the uptake of interstitial fluid, proteins, and cells from surrounding tissues. Function ○ The endothelial cells feature unique junctions that facilitate the passage of larger molecules and immune cells.  ○ This permeability is crucial for the lymphatic system’s roles in fluid absorption and immune surveillance → Primary Lymphatic System: ​Responsible for the production and maturation of lymphocytes (adaptive immunity). Ensures that B-cells and T-cells are adequately developed and functional. Primary lymphatic system consists of: ○ Bone marrow: Hematopoiesis occurs here. Both B-cells and T-cells originate here. ○ Thymus: T-cells migrate from the bone marrow to the thymus, where they mature and undergo selection processes ensuring the can recognize foreign antigens while avoiding autoimmunity → Adaptive Immune responses of Lymphocytes DNA Rearrangement ○ B and T lymphocytes rearrange their DNA to create unique antigen receptors for pathogen recognition. Clonal Expansion ○ Upon antigen binding, B and T lymphocytes rapidly multiply to fight the infection. Memory Cell Formation ○ Some lymphocytes become long-lived memory cells, enabling faster immune responses during future encounters with the same pathogen → Secondary Lymphatic System: Lymph Nodes ○ Lymph nodes act as filters for lymph fluid. They contain a high concentration of lymphocytes and other immune cells, playing a key role in immune responses. Spleen ○ The spleen filters blood, removing old or damaged red blood cells (RBCs) and recycling iron. ○ It contains lymphoid tissue that helps mount immune responses against blood-borne pathogens. Mucosa-Associated Lymphoid Tissue (MALT): This includes structures like the tonsils and Peyer’s patches, which protect mucosal surfaces from pathogens. → Cells become cancerous when a critical number of driver mutations have occurred leading to malignant transformation ○ Cancer cells have advantage over nonmutated cells -> undergo clonal proliferation ○ Cancer cells can then develop their own mutations -> heterogenous mixture of cancer cells  Hodgkin's Lymphoma- Cancer of the lymphocytes ,characterized by the Presence of Reed Sternberg cells ❖ Pathophysiology arises in a single chain of lymph nodes-> contiguous spreading to lymphoid tissue presence of Hodgkin & Reed-Sternberg cells derived from germinal center B cells – unknown trigger B cell with unsuccessful immunoglobulin gene rearrangement Loss of B cell markers Evade apoptosis d/t EBV infection, signaling pathway mutation (NF-κB) Secrete & release cytokines (IL-10, TGF-β) -> accumulation of inflammatory cells in the tumor microenvironment Inflammatory cells molecules bind to proteins on the HRS cell membrane -> allow growth & survival of HRS Tumor-associated macrophages: support HRS cell growth Express CD15 & CD30 ❖ Clinical Manifestations Most common: Painless lymphadenopathy in lower cervical chain Can present with or without fever Firm, rubbery nodes 2/3 patients have mediastinal involvement  Nonproductive cough Tracheal/bronchial compression -> airway obstruction Inflammation: elevated WBC (leukocytosis) Additional lab findings: anemia, elevated sed rate, eosinophilia, leukopenia (advanced) Non-Hodgkin's lymphoma- Cancer of the lymphocytes, primarily the white blood cells and grow abnormally and form tumors. More diverse group of blood cancers. ❖ Pathophysiology Sustained Proliferation Cancer cells express mutated proto-oncogenes (oncogenes) Proto-oncogenes regulate normal cell proliferation Oncogenes function outside of normal regulatory mechanisms -> uncontrolled proliferation Oncogenes can be activated by translocation Mechanisms for NHL development: immunosuppression, chronic antigen stimulation Chronic antigen stimulation/immunosuppression -> increased B-cell proliferation -> genetic mistakes (immunoglobulin gene rearrangements) Chromosomal translocations -> oncogenes activated (most common) Chromosomal deletion or mutation -> tumor-suppressors inactivated ❖ Burkitt Lymphoma t(8;14) translocation: Burkitt Lymphomas (cancer of the B lymphocytes) MYC proto-oncogene on chromosome 8 – present in low levels in immature lymphocytes, none in mature lymphocytes t(8;14) translocation: MYC becomes controlled by B-cell immunoglobulin gene (IG) on chromosome 14 -> increased MYC levels Drives proliferation and blocks differentiation Burkitt lymphoma: Sporadic, endemic and immunodeficiency associated variants Endemic: latent EBV infection – nearly all cases Sporadic (nonendemic): latent EBV infection – 15-20% of cases Immunodeficiency: HIV infection (25%), Solid organ transplant, Wiskott-Aldrich syndrome, ataxia-telangiectasia, Bloom syndrome -> EBV  ❖ Clinical Manifestations Lymphadenopathy (can be painful): common in neck, underarm, stomach, groin Can be extra nodal (Waldeyer ring) Burkitt: jaw/face tumors Mesenteric involvement common Non-contiguous, unpredictable spreading Site specific symptoms GI origin: abdominal pain, vomiting, ascites Chest: trouble breathing, cough Breast Cancer → Demographics Breast cancer is the leading type of cancer in women Women over 50 account for 82% of Breast Cancer cases Breast Cancer risk double in those with a first degree relative with a history of Breast Cancer Breast Cancer risk increases more if a first degree relative had an early age occurrence or had bilateral breast cancer. Breast cancer risk up to 65% in those with BRCA1 gene Men can get breast cancer but not as prevalent. Invasive Breast Cancer affects 1 in 8 women Estimated over 310,000 cases in 2024 Risk Factors: >65 Atypical Hyperplasia Genetic mutations: BRCA1, BRCA2, PALB2, TP53 Postmenopausal Late Menopause after 55 Early menarche, short menstrual cycles Estrogen or Progestin hormone therapy postmenopausal Medications: Insulin and Sulfonylureas Full-term pregnancy after 30 No full-term pregnancies Radiation to chest Dense breast tissue Never Breastfed Alcohol use Obesity Sedentary lifestyle Xenoestrogens: estrogen mimicking chemicals that are found in plastics, pesticides, detergents, fuel, and drugs. Sources of Xenoestrogens: Polychlorinated biphenyls(PCBs) Bisphenol A in polycarbonate plastics Tobacco Smoke Car exhaust Cleaning products and detergents Phthalates in plastics and cosmetics Parabens Food additives such as rBST and Zeranol Hormone replacement therapy → Normal pathophysiology General Anatomy ○ The adult female breast consists of 15 to 20 pyramid-shaped lobes, separated and supported by suspensory ○ (Cooper) ligaments. ○ Each lobe contains 20 to 40 lobules, which are further divided into numerous functional units called acini. ○ Acini are lined with epithelial cells capable of secreting milk and subepithelial cells that contract to facilitate ○ milk ejection. ○ The breast is supported by a network of blood vessels and nerves that contributes to its complex functionality. Important Components ○ Acini: The primary milk-secreting units.  ○ Lactiferous Ducts: Channels that transport milk from acini to the nipple. ○ Nipple and Areola: Contain openings for milk ejection and aid in the suction process during breastfeeding. ○ Stromal Cells: Different types of structural cells which secrete extracellular matrix (ECM) and defend tissue integrity (e.g. macrophages, adipocytes, immune cells, endothelial cells) Genetics: DNA Damage and Mutation ○ The development of most breast cancers involves DNA damage and genetic mutations. ○ Mutations and inheritance of precancerous genes such as BRCA1and BRCA2 are significant contributors ○ Approximately 25% of hereditary breast cancers are due to mutations in highly penetrant genes  ○ (BRCA1, BRCA2, PTEN,TP52, CH11, and STK11), and 2-3% are due to rare, moderately penetrant gene mutations which include CHEK2, BRIP1, ATM, and PALB2 Highly penetrant genes = 80% lifetime risk BRCA1: Located on chromosome 17, it is a tumor suppressor gene,and mutations can inhibit its function, leading to uncontrolled cell proliferation BRCA2: Located on chromosome 13, is also crucial. Males with breast cancer are more likely to have mutations in BRCA2 than BRCA1 → Breast Cancer Pathophysiology 70% of Breast Cancers are adenocarcinomas that start in the ductal/lobular epithelium. The immune system normally attacks cells with abnormal DNA or growth, but in breast cancer, this response fails, allowing tumor growth and metastasis. Breast cancer cells communicate with surrounding stromal cells via paracrine signaling by secreting growth factors and cytokines. ○ Cancer Progression Effects: These interactions promote cancer cell proliferation, blood vessel formation (angiogenesis), and metastasis. Breast tumor subcategories are defined by their responses to hormones and growth factors. Based on specific receptors, breast cancer is categorized ○ ER (Estrogen Receptor) ○ PR (Progesterone Receptor) ○ HER2 (Human Epidermal Growth Factor Receptor 2) types → Hormonal Influence and Breast Cancer Estrogens: ○ Act as initiators and accelerators of breast cancer. ○ Influence the susceptibility of the breast epithelium to environmental carcinogens. ○ Control the differentiation of mammary gland epithelium, regulating stem cell division. Progesterone: ○ Plays a complex role in breast physiology and carcinogenesis. ○ Cell proliferation in the breast occurs during the luteal phase of the menstrual cycle, contributing to changes in the microenvironment. Key Effects: ○ Endogenous estrogen can promote the progression of estrogen receptor-negative (ER-negative) breast cancer by stimulating cancer-associated fibroblasts to secrete factors that engage bone marrow–derived cells to the tumor microenvironment. This promotes proliferation, angiogenesis, and metastasis.  ○ Estrogen can modify immune function in the mammary gland, promoting a proinflammatory phenotype in macrophages and immunosuppression. → Reason for Metastasis Breast cancer has a high rate of metastasis due to its Tumor Microenvironment (TME) and Epithelial-Mesenchymal Transformation –EMT Normal epithelial cells, cancer cells, immune cells, cytokines, endothelial cells, fibroblasts, and macrophages make up the TME. EMT is a biochemical process that changes epithelial cells into mesenchymal cells which enables them to migrate and invade easier. EMT enables tumor progression by : ○ Enabling tissue plasticity and allowing cells to gain migratory/invasive traits ○ Suppressing cell death and senescence ○ enabling resistance to chemotherapy and radiation ○ Reactivating during wound healing and cancer metastasis → Epithelial-Mesenchymal Transformation Breast tumor cells enhance their migration through the induction of epithelial- mesenchymal transition (EMT). EMT is also called "transdifferentiating" and is the process where cells lose their cell adhesion ability and their polarity During EMT, levels of N-cadherin and vimentin rise, while E-cadherin levels decrease, facilitating EMT-driven breast tumor invasion.  Epithelial-Mesenchymal transition can take place in 2 different ways. ​It can happen through single cell dissemination It can also happen as a group in Collective Migration → Clinical Manifestations Change in breast size, shape, color, or texture Peau D'orange Breast Asymmetry Retracted nipple Nipple discharge Flaking, crusting, or peeling of skin Hardened, immovable mass underneath breast → Infiltrating Carcinoma Ductal: Fibrous firm mass that has chalky streaks. Mucinous: Usually >3cm in diameter. Encapsulated and circumscribed. Two types: Pure and Mixed. Pure type has mucin surrounding it. Most common in women >70 Medullary: Large tumors 7-8 cm in diameter. Encapsulated and enveloped by a lymphocytic inflammatory infiltrate  Tubular: Well-differentiated with organized tubules at the center of the mass called a Stroma. Can be linked to noninfiltrating ductal carcinoma. Does not often metastasize and is rare in general Adenoid cystic: Mass that emerges from the nipple and areola that is well circumscribed Metaplastic: Bone or Cartilage involvement, tumors are mixed or osteosarcomas Squamous Cell: Begins in the epithelium of the ducts Carcinoma of the Mammary Duct Papillary: Many areas of cystic masses often accompanied with hemorrhage; can be some skin involvement Intraductal: Frequently associated with inflammation, characterized by well-defined tumors made up of well- differentiated tumor cells that rarely cause skin ulcerations. → Carcinoma of the Mammary Lobules Lobar Carcinoma in Situ: Found in those with Fibrocystic disease and usually appears in the upper breasts. Infiltrating Lobular Carcinoma: Firm mass that has chalky streaks and infiltrates from the ducts. Paget's Disease: Paget cells come from the duct and take over the nipple. A palpable lesion is usually found under the nipple. Eczema like red scaly rash that starts at the nipple and moves into the areola. Inflammatory Carcinoma: Diffuse within the breast tissue, present with generalized skin edema and will usually metastasize to the axilla. → Sarcoma of the Breast Cystosarcoma Phyllodes: Large, >17cm in diameter. Do not usually metastasize to lymph nodes. Skin ulcerates and bleeds often. Fibrosarcoma: Originates firm connective tissues, firm and does not involve the nipple or the skin. Ex: Liposarcoma, Angiosarcoma → Male Breast Cancer BRCA 2 Carriers have 80 times more risk than the rest of the population Usually Hormone receptor positive, HER2 negative Reporting and staging similar to female breast cancer Generally, efforts need to be made to distinguish metastatic lesions to the breast with primary carcinomas. → Triple Negative Breast Cancer This is a subtype that is negative for Estrogenreceptors, Progesterone receptors, and HER2. These don't respond to hormonal or HER2-targetedtherapies Prostate Cancer  Need early intervention and discussing risk factors with prostate cancer​ Age is independent risk factor (older age -> higher risk)​ Different mutations express differently ​ Chronic inflammation includes autoimmune disease​ Diet – higher char grilled meats, deficiency in vitamin E, D, calcium, etc.​ Hormonal influence – amount of testosterone metabolized into estrogen especially in peripheral tissues, occurs more with age -> can turn off tumor regulating receptors​ Senescence: aging vascular structures, e.g. testicular metabolic system – are things replicating and metabolizing correctly? - influence chronic inflammation TESTOSTERONE ○ Gonadal development​  ○ Sperm production​ ○ Secondary sex characteristics​ ○ Hair texture and distribution​ ○ Muscle mass​ ○ Bone density​ ○ Libido/sex drive​ ○ Red blood cell production​ ○ Vascular smooth muscle regulation​ ○ Nitric Oxide ANDROGEN AND ANDROGEN RECEPTORS ○ Males have higher Hgb & hematocrit naturally dt testosterone (w/ role in RBC production) ​ ○ DHEA – precursor to testosterone; DHE travel via bloodstream to prostate gland to be enzymatically converted to testosterone [in prostate gland, DHEA is not metabolically activated (not bind to androgen receptor) - when it's further converted from testosterone into metabolically active DHT via 5 alpha reductase then bind to receptors in prostate gland & promote production of proteins that'll be released and contribute to formation of final ejaculate delivered during intercourse for sexual reproduction) ​ ○ --Testosterone once formed (can form in different organs, like lung, liver, bone); DHEA can go to other places within the body​ ○ --Testosterone metabolized into estrogens with inc in age – bind to and active estrogen receptors via aromatase ​ ○ >>Tmnt: aromatase inhibitors with prostate cancer​ ○ When DHT activates androgen receptors – acts as SECOND MESSENGER (responsible for signaling to self to prostate cells going into  DNA causing transcription/translation of different proteins helping prostate to function ​ ○ --DHT is both Autocrine (self signaling) & Paracrine (signaling to adjacent cells to ensure working in unison together) Normal Prostate Structure and Feature Conversion of Testosterone to Estrogens  ○ Spermatozoa – synthesized in testes -> vas deferens -> seminal vesicles -> fluid added that's high in glucose to feed/give energy to spermatazoa to survive journey to vagina in uterus for implanation (sexual reprodu)​ ○ Urethra joins with seminal vesicles - as it travels through prostate, picks up prostatic fluid to add volume for sperm to swim & alkaline to ensure the sperm survives to endure acidic vaginal environment when it arrives​ ○ Zone of prostate​ ○ --Peripheral zone: 70% cancers occur, where working cells largely epithelium; (adenocarcinoma – glandular form of cancer)​ ○ --Central zone: ejaculatory ducts travel through​ ○ --Transitional zone: surrounds urethra; where most benign prostatic hypertrophy occurs – cells getting large and causing obstruction of urethra ​ ○ In stromal/structural cells of prostate, primarily fibrous & muscular tissue present ​ ○ --Estrogen receptors in prostate gland largely in stroma itself​ ○ >Alpha estrogen receptors responsible for sperm maturation [bad things seen w/ prostate ca is dt effects it has on alpha receptors] ​ ○ >Beta estrogen receptors – bone density and libido (receptors in brain as well); largely antiproliferative Prostate Cancer Pathogenesis: Theories for Tmnt Approach ○ Excessive androgen production outside the testes ○ Altered form and function of prostatic androgen receptors ○ Role of estrogen, aromatase (conversion of testosterone), prostatic estrogen receptors ○ Function of the stromal cells (location of estrogen receptors) Mechanisms ○ Epithelial Mesenchymal Transition Changes in cellular polarity, adhesion (change in paracrine stimulation), morphology, gene expression (translational), inc invasion, migration, vascularity/angiogenesis ○ Prostatic Intraepithelial Neoplasia (PIN) Chronic inflammation, cellular injury Tied to autoimmune disease *when have high rate of neoplasia (new abnormal cell growth) -> inc risk of developing cancer Mutations leading to Prostate Cancer  ○ Common mutations​ Oncogene MYC (c-MYC)​ Promotes cellular growth and metabolism​ ​BRCA2 (7-8x risk of developing prostate cancer)​ Transcription factor (mRNA)​ Mutation of tumor suppressor gene [turned off]​ ​HOX13 (3x risk of developing prostate cancer)​ Signaling, protein synthesis and regulation TP53 gene​ Codes for p53 protein​ Regulates protein synthesis and cellular repair​ ​TMPRSS2- Androgen related cell surface serine protease Invasion, degradation of ECM, tumor growth, metastasis​ Notes ​ Oncogene: promote tumor growth, initiation, and malignant transformation​ Androgen signaling​ --unable to repair damaged cells or dysfunctionally repair them --> cancer​ Prostate specific antigens (antigens in prostatic fluid) - can be indicative of epithelial & cellular injury that can result in cancer ​ ​P53 involved with regulation of protein synthesis and repair​ Nonsense dt mutation in code for halting protein production – see too much of protein being synthesized -> cancer ​ ETMPRSS2 – presence of abnormal protease – lead to invasion, breakdown of extracellular matrix of prostate -> tumor growth and metastasis Clinical Manifestations of Prostate Cancer  R/T Bladder Outlet Obstruction (BOO)​ Typically late stage​ PROGRESSIVE:​ Nocturia​ Incomplete emptying/retention​ Slow urine stream, hesitancy​ Dysuria Bowel symptoms (constipation, obstruction)​ Sexual dysfunction​ Bone pain, confusion, edema (lymphatic obstruction)- signs of metastasis​ Notes Symptoms can be differentiated from UTI or BPH (since once shows up, it gets worse (it doesn't stabilize, not slow)) - inc rapidly depending on aggressive nature of tumor ​ If urine sits, will get infected (dysuria) Metastasis Lymph, Lung, Liver, Bone, Brain Summary for Prostate Cancer ○ Prostate Cancer is common and associated with the aging process in men​ ○ Mutations causing prostate cancer are often germline/familial but environmental risk factors play a huge role​ ○ Caused by a wide variety of genetic mutations​ ○ Approaches to treatment currently based on androgen receptor pathway inhibitors. Tumors often become “castration resistant”​ Even if stop the tumor – it finds a way to promote continued survival ("castration resistant") ○ Consider age, family history, and exposures to consider how best to prevent prostate cancer and treat early when it occurs​ Lung Cancer  Definition: “tumors originating in the lung parenchyma or within the bronchi (bronchogenic carcinoma)” Two types ○ Non-small cell carcinoma (NSCLC) 85% of LC cases ○ Small cell carcinoma (SCLC)/Neuroendocrine tumors 15% of LC cases Impact: leading cause of cancer-related death globally NON-SMALL CELL CARCINOMA 1. Squamous cell carcinoma (slow growth rate) ○ Typically located near the hila and project into bronchi​ Hila – wedge shaped area in center of lung, blood vessels, lymphatics, nerves enter and exit ○ Pneumonia and atelectasis are often associated​ ○ Well localized and tend not to metastasize​ 2. Adenocarcinoma (moderate growth rate)​ Tumor arising from the glands​ Epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, and other tyrosine kinase inhibitors are common*​ Develop in a stepwise fashion​ 3. Large cell undifferentiated carcinoma (rapid growth rate, metastasize early)​ Transformed epithelial cells that have lost clear evidence of maturation​ Arise from squamous, glandular, or neuroendocrine precursor cells​ 4. Neuroendocrine tumors (arise from bronchial mucosa) ○ Small cell carcinoma (most common) VERY RAPID​ Central in origin (hilar and mediastinal)​ Metastasize early and widely​ Associated with ectopic hormone production​ Paraneoplastic syndromes​ ○ Large cell neuroendocrine carcinoma (rare)​ ○ Bronchial carcinoids (rare) 5. Mesothelioma (rare) ○ Associated with asbestos exposure​ ○ Arise from mesothelial cells that line the pleura​  Epidemiology ○ Lung cancer is the most diagnosed cancer globally, making up 12.4% of all cases, and is the top cause of cancer deaths​ ○ In the U.S., over 234,000 cases are​expected annually.​ While lung cancer was once mostly seen in developed countries, nearly 50% of new cases now occur in underdeveloped regions.​ In the U.S., men have higher mortality rates than women, and African American males have a higher age-adjusted mortality rate compared to Caucasian males. Incidence ○ In 2018, the US saw 234,000 new lung cancer cases, with 121,680 in men and 112,350 in women. ○ Lung cancer ranks as the second most common cancer in men and women, after prostate and breast cancer.​ ○ The incidence rates in men have dropped since 1982, thanks to anti-smoking efforts, while women’s rate saw a slower decline, starting in the 2000s. Etiology ○ Smoking is the leading cause of lung cancer, responsible for 90% of cases.​ ○ Risk is highest among males who​smoke, especially with added exposure to other carcinogens.​  Passive smoking increases lung cancer by 20-30%​ Other factors include radiation treatments, exposure to metals (arsenic), and lung disease such as pulmonary fibrosis.​ Asbestos and radon exposure are also linked, with asbestos risk varying by fiber type. Risk Factors ○ Age Men 85-89; Women 75-89 Senescence ○ Gender: Male > Female ○ SES: lower status = higher risk ○ Smoking: 90% attributed ○ Tobacco carcinogen exposure ○ Radon exposure: 10% [radiation], X-rays ○ Occupational: asbestos (e.g. miners) ○ Air quality: pollution (e.g. smog) ○ Lung damage: TB, HIV, infections Diseases (e.g. COPD) ○ Genetics: Family history & mutations boost risk Normal Biology Lungs ○ Normal Lung Structure​ Bronchi and Bronchioles​ Alveoli​- gas exchange Surfactant Production​- produced by Type II alveolar cells, reduce surface tension, prevent collapse Pleural space​ Hila​-- wedge shaped area in center of lung, blood vessels, lymphatics, nerves enter and exit Cellular Regulation​ Cell Cycle Control​-- normal lung cells tightly regulated growth & division cycles controlled by tumor suppressor genes, p53 Division cycles controlled by protooncogenes Apoptosis​-- programmed cell death Tissue Repair and Remodeling​-- following injury via inflammation and regeneration processes ○ Immune Surveillance - macrophages, leukocytes - monitor pathogens & abnormal cells and role in preventing cancerous neoplasms Cancer Biology ○ The microenvironment of a tumor is a heterogeneous mixture of cells, both cancerous and benign​