D’YOUVILLE COLLEGE
PMD 604 - ANATOMY, PHYSIOLOGY, PATHOLOGY II
Lecture 7: Normal cell proliferation, healing, abnormal cell proliferation,
neoplasias
Robbins chapters 3 & 6
1.
Cellular Proliferation & Cell Cycle:
• normal balance of tissue growth: adult organs & tissues maintain a constant
size through a balance between proliferation & apoptosis (fig. 3 – 2 & ppt. 1)
- repair of tissue injury may entail regeneration or scar formation or often a
combination of these, dependent upon tissue involved and the extent of injury to the
extra cellular matrix (ECM) (fig. 3 – 1 & ppt. 2)
- cell cycle regulates growth in response to internal signals (cyclins & cyclin
dependent kinases [CDK]) and external signals (growth factors); cycle (dominated by
interphase between mitotic divisions) is subdivided into three periods: G1, S , G2; a
cell may become arrested in G1 (or transfer to a G0 period (figs. 3 – 3, 6 – 19 & ppts.
3 & 4)
- G1 & G2 periods (prereplication growth & premitotic growth periods) feature
protein synthesis & other routine metabolism; G1 prepares for DNA synthesis; G2
prepares for mitosis
- S period - DNA synthesis
2.
Healing:
• tissue components: functional cells (parenchyma) supported by connective
tissue & blood vessels (stroma)
• proliferative capabilities of different tissues: labile, stable & permanent
tissues
- labile tissues normally maintain high mitotic activity (e.g., bone marrow,
lymphoid tissue, surface epithelia); regenerate rapidly to replace losses through
apoptosis
- stable tissues maintain slower or temporarily arrested mitotic activity (e.g.,
glandular tissue [=parenchyma + stroma], smooth muscle, bone, vascular
endothelium & fibroblasts), but may be stimulated to resume mitotic activity (transfer to
G1 from G0, but may return to G0)
- permanent tissues have ceased (& usually cannot resume) mitotic activity
(transferred permanently into G0); thus are incapable of regeneration
• growth factors (GFs): (table 3 – 1)
- ligands that bind to external receptors to activate changes in intracellular
activity (particularly at check points of cell cycle) (fig. 3 – 6 & ppt. 5)
PMD 604, lec 7
- p. 2 -
- activation of growth controlling genes (protooncogenes) is a frequent
cellular response to binding of a growth factor
- secretion of GFs may be from cells of injured tissue, from various leukocytes,
including macrophages at an inflammation site; GFs may act upon secreting cell
(autocrine pattern), or upon near neighbor cells (paracrine pattern), or upon distant
target cells via bloodstream (endocrine pattern) (fig. 3 – 5 & ppt. 6)
PMD 604, lec 7
- p. 3 -
• extracellular matrix (ECM):
- functional roles: includes interstitial matrix & basement membranes and
provides support for cells, directs organization of pattern of growth (essential for
regeneration) and provides a reservoir of GFs (fig. 3 – 8 & ppt. 7)
- constituents: collagen, elastin, proteoglycans & glycoproteins (fig. 3 – 7 & ppt.
8)
• repair (healing):
- regeneration (compensatory hyperplasia) involves proliferation of surrounding
healthy parenchyma, to replace lost tissue and assume normal function
- regenerative capability is possessed by labile and stable tissues, but
not by permanent tissues
- regeneration requires intact ECM
- stimulated by GFs, such as colony stimulating factors (CSFs), tumor
necrosis factor (TNF) and interleukin-6 (IL-6)
- fibrosis (scar formation) occurs in tissues that are unable to regenerate
(resulting tissue is nonfunctional); fibroblasts (connective tissue cells of stroma)
produce extracellular matrix (ECM); ECM directs orientation and maturation of new
collagenous fibers so as to maximize tensile strength of the scar
- angiogenesis (revascularization): involves endothelial budding of
remaining healthy blood vessels and coalescence of buds to establish new vascular
network; additional wall layers (of arterioles & venules) are added to outer surface
(fig. 3 – 12 & ppt. 9)
- organization involves phagocytic removal of clots and debris from injury
site, followed by replacement with scar
- granulation tissue (fig. 3 – 14 & ppt. 10) is associated with the granular
appearance of exudate in which new blood vessels are developing accompanied by fibroblasts
and leukocytes
• cutaneous wound healing (fig. 3 – 15 & ppt. 11):
healing by first intention occurs with narrow wounds, such as surgical
incisions or cuts; small scar and minimal wound contraction result
healing by second intention occurs with more extensive wounds, abscesses or
ulcers; larger clot, more intense inflammation, more extensive granulation tissue & greater
wound contraction result
• complications of healing:
- contracture: due to exaggerated wound contraction
- adhesions: due fibrosis uniting adjoining serous membranes
- dehiscence: (usually abdominal): excessive pressure may reopen wound
before healing is complete; risk of infection, herniation
- keloids: due to excessive fibrosis producing raised welt on surface
- proud flesh: due to excessive development of granulation tissue; may
delay healing
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- p. 4 -
• summary of healing: (fig. 3 – 18 & ppt. 12)
PMD 604, lec 7
3.
- p. 5 -
Abnormal Patterns of Proliferation:
• metaplasia: (fig. 1 – 5 & ppt. 13) (previously discussed in lec. 3)
• dysplasia: change in growth pattern that is abnormal in terms of function,
variations of cell size & nuclear characteristics (pleiomorphism)
- not always reversible & often treated as a precancerous change (some
lesions known as carcinoma in situ) (ppt. 14)
• neoplasia: irreversible departure from normal growth; afflicts over 3 in 10;
at least 1 in 4 die of it, greater numbers die with it; major health threat (fig. 6 – 13 & ppt.
15)
- growth is described as autonomous: independent of normal balancing
signals (GFs) that regulate proliferation of cells
4.
Terminology & tumors:
• oncology: (oncos = tumor) - study of neoplasia - condition characterized by
loss of normal mitotic controls
• general characteristics & nomenclature: classified as benign or malignant
(fig. 6 – 12 & ppt. 16)
- tumor cells in varying degrees, a) resist apoptosis, b) are insensitive to growth
inhibitors, c) provide own growth factors, d) can become invasive & metastasizing, e) can
stimulate angiogenesis & f) have unlimited proliferative capacity (fig. 6 - 17 & ppt. 17)
- suffix -oma signifies tumor; benign growths named according to specific
tissue of origin, e.g., glandular --> adenoma, bone --> osteoma, fat --> lipoma, &
connective tissue --> fibroma
- malignancies include word roots carcino- for tumors originating from
ectodermal and endodermal embryonic origins (epithelial or neural tissues) or sarcofor tumors originating from mesodermal origin (connective tissues), e.g.
adenocarcinoma, osteosarcoma, fibrosarcoma (table 6 - 1)
• benign tumors: usually slower growing; growth consolidates surrounding
parenchyma & stroma producing capsule (encapsulated tumors); some benign
growths are unencapsulated, but a generally well-defined cleavage plane is evident
- discrete and localized character usually renders less damage to normal
tissues & better prognosis for treatment (including surgical removal)
- often well differentiated & normal looking; may have normal function or
hyperfunction
- although most are relatively innocuous, some may cause disease or serious
disruptions of normal growth & function
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- p. 6 -
• malignant tumors: faster growing, invasive & diffuse, poorly organized
abnormal cells (= pleiomorphism) or cells that are less differentiated or
undifferentiated (= anaplasia) (fig. 6 – 5 & ppt. 18); some overlap of features compared
with benign
- metastasizing (see below)
- tumor cell reduced adhesiveness facilitates invasiveness (fig. 6 – 27 & ppt.
19); growth follows path of least resistance (ppt. 20)
- tumor growth rate varies (seldom as fast as regeneration in healing or
embryonic growth), but rate of growth usually exceeds rate of most normal tissues;
anaplasia usually corresponds with faster growth rate
- metastasis: loosely adherent cells break free from tumor and may enter
lymphatic passages, bloodstream, or body cavities (emboli); circulate until trapped in
smaller vessel where they invade and establish secondary growth (fig. 6 - 26 & ppts.
21, 22 & 23); often leads to predictable sites for secondary tumors (ppt. 24)
- effects of tumors: compression injuries & obstructions interfere with
normal functions of surrounding tissues (ppt. 25)
- abnormal adhesions may restrict normal organ functions (ppt. 26)
- damage to basement membranes & extracellular matrix may impair
healing
- interference with production of normal defenses may cause an
increase in infections
- disruption of normal regulation of marrow, possibly causing anemias,
impaired immune responses, etc. (ppts. 27 & 28)
- collectively, impairments due to tumors may cause a general weakness &
loss of weight combined with loss of appetite (= anorexia - cachexia syndrome)
5.
Carcinogenic Transformation:
• oncogenes: genes normally coding for proteins that regulate cell growth and
DNA repair processes (protooncogenes or tumor suppressor genes or genes
regulating apoptosis or genes governing DNA repair) may become defective;
abnormal products of such genes (oncogenes) may result in uncontrolled cell growth,
impaired suppression of cell growth, impaired regulation of apoptosis (ppts. 29 & 30) &/or
accumulation of DNA damage (fig. 6 – 22 & ppt. 31)
- several steps of cell damage (involving participation of initiators &
promoters) are needed to advance transformation & tumor progression (figs. 6 - 15, 6
- 16 & ppts. 32, 33 & 34)
• initiators & promoters: environmental agents, e.g., solar &/or ionizing
radiations, certain viruses & numerous chemical agents (carcinogens; table 6 - 4) can
provoke transformation to neoplasia (oncogenesis or carcinogenesis); whether these
agents act as initiators or promoters or render cells more vulnerable to initiators or
promoters is poorly understood (ppt. 35)
PMD 604, lec 7
6.
- p. 7 -
Diagnosis & Treatment:
• diagnosis of cancer: relies on cellular morphology exhibited in biopsies, e.g.
Pap smears (fig. 6 – 34 & ppt.36), or tests for tumor antigens, PSA, or other tumor
products in blood
-morphological characteristics of tumors are used for tumor grading
(scored from I to IV); this system has predictive value for survival prognoses
• staging of tumors: tumor staging is a practice based on characteristics of
solid tumors; it relies on degree of localization, invasiveness, and extent of metastasis
- scored from I to IV; although not universally applicable, the TNM staging
system is internationally recognized (ppt. 37)
• cancer therapy:
- surgery has greatest prospect for success with benign tumors or malignant
tumors that are well localized; a diffuse character may necessitate removal of
surrounding healthy tissue (with possible severe effects); likelihood of metastasis
necessitates removal of regional lymph nodes serving the tumor site
- radiation damages healthy tissue as well as destroying tumors, so
techniques to maximize tumor dosage while minimizing exposure of normal tissues
are continually being sought; tumors vary in their sensitivity to radiation treatments
as do normal tissues
- chemotherapy (ppt. 38) relies on mixtures of chemicals primarily aimed at
arresting cell division in tumors and promoting removal of damaged tumor cells;
tumors and cells within tumors vary in their sensitivity/resistance to chemotherapy;
also normal tissues are also victimized by chemotherapy, e.g., labile tissues such as
hair follicles, gastrointestinal mucosa, & bone marrow
- immunotherapy: sensitization of immune system against tumor specific
antigens; at one time a basis for great optimism in cancer therapy, appears to have
fallen short of its anticipated promise (ppts. 39 & 40)