34.

Vascular dissemination and homing of tumor cells (Page 308-304)

Once in circulation, tumor cells are vulnerable to destruction by a variety of

mechanisms, so they tend to aggregate in clumps to enhance survival and implantability
 There is homotypic adhesion among tumor cells as well as heterotypic adhesion
b/t tumor cells and blood cells, particularly platelets (tumor cells may also bind
and activate coagulationfactors, to form emboli)
Arrest and extravasation of tumor emboli at distant sites involves adhesion to the
endothelium and then egress through the basement membrane
 Involves adhesion molecules (integrins, laminin receptors) and proteolytic
enzymes
 CD44 adhesion molecule is expressed on normal T lymphocytes and is used to
migrate to selective sites in lymphoid tissue by binding to hyaluronate on high
endothelial venules; overexpression of CD44 may favor metastatic spread
 The site at which the circulating tumor cells leave the capillaries to form
secondary deposits is related partly to the anatomic location of the primary
tumor, with most metastases occurring in the first capillary bed available to the
tumor. Natural pathways of drainage do not wholly explain the distribution of
metastases though, and some cancer cells preferentially spread to organs
(“organ tropism), which may be related to the following mechanism:
 Tumor cells may have adhesion molecules whose ligands are expressed
preferentially on the endothelial cells on the target tissue
 Chemokines have an important role in determining target tissues for
metastasis, and some target organs may liberate chemoattractants that
recruit tumor cells to the site.
 Target tissue may be a nonpermissive environment for growth of tumor
seedlings, so they avoid being the site of metastasis
At the new site, tumor cells must proliferate, develop a vascular supply, and evade host defense
Tumor cells secrete cytokines, growth factors, and ECM molecules that act on the resident
stromal cells to make the metastatic site habitable for the cancer cells.

35. Mechanism of Tumor Metastasis and (Page 309)

The clonal evolution model suggests that as mutations accumulate in genetically unstable cancer
cells and the tumor become heterogeneous (Fig. 7-38A), a rare subset of tumor cell subclones
acquires a pattern of gene expression that is permissive for all steps involved in metastasis.
A subset of breast cancers has a metastatic gene expression signature similar to that found in
metastases, although no clinical evidence for metastasis is apparent. It is hypothesized that in
these tumors with a “metastasis signature” most if not all cells develop a predilection for
metastatic spread during early stages of carcinogenesis (Fig. 7-38B).
A third idea that combines the two above supposes that the metastatic signature is necessary
but not sufficient for metastasis, and that additional mutations are needed for metastasis to
occur (Fig. 7-38C).
Finally, there is evidence the capacity for metastasis involves not only properties intrinsic to the
cancer cells but also the characteristics of their microenvironment, such as the components of
the stroma, the presence of infiltrating immune cells, and angiogenesis (Fig. 7-38D).
 A metastasis suppressor gene is defined as a gene whose loss promotes the development of
metastasis without an effect on the primary tumor. At least a dozen genes lost in metastatic
lesions have been confirmed to function as “metastasis suppressors.” Their molecular functions
are varied and not completely clear; however, most appear to affect various signaling pathways.
SNAIL and TWIST (metastasis oncogenes): which encode transcription factors whose primary
function is to promote epithelial-to-mesenchymal transition (EMT).
EMT: carcinoma cells downregulate certain epithelial markers (e.g., E-cadherin) and upregulate
certain mesenchymal markers (e.g., vimentin and smooth muscle actin).
These changes are believed to favor the development of a promigratory phenotype that is
essentialfor metastasis. Loss of E-cadherin expression seems to be a key event in EMT, and
SNAIL and TWIST are transcriptional repressors that downregulate E-cadherin expression. EMT
has been documented mainly in breast cancers; whether it is a general phenomenon in other
solid tumors remains to be established.

36. Epigenetics (page 319; see table 7-9)

Epigenetic: factors other than DNA sequence that regulate gene expression
Silencing of tumor suppressor genes by local hypermethylation of DNA. Some cancer cells
exhibit selective hypermethylation of the promoters of tumor suppressor genes that results in
their transcriptional silencing. Typically, hypermethylation occurs on only one allele and the
function of the other copy of the affected tumor suppressor gene is lost through another
mechanism, such as a disabling point mutation or a deletion. One of several examples of a
tumor suppressor gene that is hypermethylated in several cancers is CDKN2A, which you will
recall is a complex locus that encodes two tumor suppressors, p14/ARF and p16/INK4a, that
enhance p53 and RB activity, respectively.
Global changes in DNA methylation. In addition to local hypermethylation of tumor suppressor
genes, many tumors exhibit abnormal patterns of DNA methylation throughout their genomes,
sometimes in the form of hypermethylation and other times as hypomethylation. Tumors
commonly exhibiting abnormal DNA methylation, such as acute myeloid leukemia, sometimes
have mutations in genes encoding DNA methyltransferases or other factors that influence DNA
methylation (Table 7-9), suggesting that the observed alterations have a genetic basis. The most
obvious potential consequence of global changes in methylation is altered expression of
multiple genes, which may be overexpressed or underexpressed compared to normal depending
on the nature of local changes. In addition, however, mice engineered to have hypomethylated
genomes also exhibit chromosomal instability; thus, altered DNA methylation may contribute to
tumorigenesis in several ways.
Changes in histones. Cancer cells often demonstrate changes in histones near genes that
influence cellular behavior. As with changes in DNA methylation, in an increasing number of
instances it appears that these alterations have a genetic basis, being attributable to mutations
that affect the activities of protein complexes that “write”, “read” and “erase” histone marks, or
that position nucleosomes on DNA (Table 7-9). Details have yet to emerge, but it is virtually
certain that these lesions somehow alter the expression of sets of genes that contribute to the
malignant phenotype.

37. Routes of Metastases (Page 273)

Pathways of Spread
o Seeding of body cavities & surfaces
 cavities and surfaces may occur whenever a malignant neoplasm
penetrates into a natural “open field” lacking physical barriers. Most
 often involved is the peritoneal cavity (Fig. 7-15), but any other cavity—
pleural, pericardial, subarachnoid, and joint spaces—may be affected.
Such seeding is particularly characteristic of carcinomas arising in the
ovaries, which, not infrequently, spread to peritoneal surfaces, which
become coated with a heavy cancerous glaze. Remarkably, the tumor
cells may remain confined to the surface of the abdominal viscera
without penetrating into the substance. Sometimes mucus-secreting
appendiceal carcinomas or ovarian carcinomas fill the peritoneal cavity
with a gelatinous neoplastic mass referred to as pseudomyxoma
peritonei
o Lymphatic Spread
 Transport through lymphatics is the most common pathway for the
initial dissemination of carcinomas
 Sarcomas may also use this route. Tumors do not contain functional
lymphatics, but lymphatic vessels located at the tumor margins are
apparently sufficient for the lymphatic spread of tumor cells. The
emphasis on lymphatic spread for carcinomas and hematogenous
spread for sarcomas is misleading, because ultimately there are
numerous interconnections between the vascular and the lymphatic
systems. The pattern of lymph node involvement follows the natural
routes of lymphatic drainage. Because carcinomas of the breast usually
arise in the upper outer quadrants, they generally disseminate first to
the axillary lymph nodes. Cancers of the inner quadrants drain to the
nodes along the internal mammary arteries. Thereafter, the
infraclavicular and supraclavicular nodes may become involved.
Carcinomas of the lung arising in the major respiratory passages
metastasize first to the perihilar tracheobronchial and mediastinal
nodes. Local lymph nodes, however, may be bypassed—so-called skip
metastasis—because of venous-lymphatic anastomoses or because
inflammation or radiation has obliterated lymphatic channels. (need
further readings)
o Hematogenous spread
 typical of sarcomas but is also seen with carcinomas
 Arteries, with their thicker walls, are less readily penetrated than are veins.
Arterial spread may occur, however, when tumor cells pass through the
pulmonary capillary beds or pulmonary arteriovenous shunts or when
pulmonary metastases themselves give rise to additional tumor emboli. In
such vascular spread, several factors influence the patterns of distribution of
the metastases. With venous invasion, the bloodborne cells follow the
venous flow draining the site of the neoplasm, and the tumor cells often
come to rest in the first capillary bed they encounter. Understandably the
liver (Fig. 7-17) and the lungs (Fig. 7-18) are most frequently involved in such
hematogenous dissemination, because all portal area drainage flows to the
liver and all caval blood flows to the lungs. Cancers arising in close proximity
to the vertebral column often embolize through the paravertebral plexus,
and this pathway is involved in the frequent vertebral metastases of
carcinomas of the thyroid and prostate
o
38. Classes of tumor Antigens (Page 310)

Tumor Antigens description

Products of mutated gene Encode variant genes that have never
been seen by the immune system and
are thus recognized as nonself.
“passengers,” mutations that are
neutral in terms of cancer cell fitness
and thus unrelated to the transformed
phenotype.
products of altered protooncogenes,
tumor suppressor genes, and
“passenger” genes are translated in the
cytoplasm of tumor cells, and like any
cytoplasmic protein, they may enter the
class I MHC antigen-processing pathway
and be recognized by CD8+ T cells.
Overexpressed or aberrantly expressed tyrosinase, an enzyme involved in
cellular proteins melanin biosynthesis that is expressed
only in normal melanocytes and
melanomas.
Tyrosinase is normally produced in such
small amounts and in so few normal
cells that it is not recognized by the
immune system and fails to induce
tolerance.
Cancer-testis antigen
MAGE antigens are expressed by a
variety of tumor types. For example,
MAGE-1 is expressed on 37% of
melanomas and a variable number of
lung, liver, stomach, and esophageal
carcinomas. There are several other
members of the MAGE family, variously
called RAGE, GAGE, and other fanciful
acronyms.
Tumor antigens produced by oncogenic viruses produce proteins that are
viruses recognized as foreign by the immune
system
The most potent of these antigens are
proteins produced by latent DNA
viruses; examples in humans include
human papilloma virus (HPV) and
Epstein-Barr virus (EBV).
CTLs recognize antigens of these viruses
and that a competent immune system
plays a role in surveillance against virus-
 induced tumors because of its ability to
recognize and kill virus-infected cells
Oncofetal antigens expressed at high levels on cancer cells
and in normal developing (fetal) tissues
Although originally believed to be
completely specific for tumors and fetal
tissues, as techniques for detecting
these antigens have improved, it
became clear that their expression in
adults is not limited to tumors
Although originally believed to be
completely specific for tumors and fetal
tissues, as techniques for detecting
these antigens have improved, it
became clear that their expression in
adults is not limited to tumors
Altered cell surface glycolipids and altered molecules include gangliosides,
glycoproteins blood group antigens, and mucins.
Mucins are high-molecular-weight
glycoproteins containing numerous O-
linked carbohydrate side chains on a
core polypeptide.
Several mucins have been the focus of
diagnostic and therapeutic studies,
including CA-125 and CA-19-9,
expressed on ovarian carcinomas, and
MUC-1, expressed on both ovarian and
breast carcinomas.
Cell type–specific differentiation antigens. Differentiation antigens- specific for
particular lineages or differentiation
stages of various cell types.
various cell types. Such differentiation
antigens are typically normal self-
antigens,and therefore they do not
induce immune responses in tumor-
bearing hosts
targets for immunotherapy and for
identifying the tissue of origin of
tumors. There are now several
examples of monoclonal antibodies
that recognize cell type specific
antigens that are highly effective anti-
tumor agents.

39. Effector Systems (Page 312)

Important: Several mucins have been the focus of diagnostic and therapeutic studies, including
CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on both ovarian
and breast carcinomas.

Cytotoxic T lymphocytes antitumor effect of cytotoxic T cells reacting

against tumor antigens is well established in
experimentally induced tumors. In humans,
CD8+ CTLs have a clear protective role against
virus-associated neoplasms (e.g., EBV- and
HPV-induced tumors), and several studies
have shown that the number of tumor
infiltrating CD8+ T cells and the presence of a
“genes signature” associated with CD8+ CTLs
correlates with a better prognosis in a variety
of cancers, not only those caused by
oncogenic viruses
Natural killer cells NK cells are lymphocytes that are capable of
destroying tumor cells without prior
sensitization
and thus may provide the first line of defense
against tumor cells. After activation with IL-2
and IL-15,
NK cells can lyse a wide range of human
tumors, including many that seem to be
nonimmunogenic for T cells. While the
importance of NK cells in host response
against spontenous tumors is still not well
established, cytokines that activate NK cells
are being used for immunotherapy.
Macrophages Activated macrophages exhibit cytotoxicity
against tumor cells in vitro. T cells, NK cells,
and macrophages may collaborate in
antitumor reactivity,
because interferon-γ, a cytokine secreted by
T cells and NK cells, is a potent activator of
macrophages. Activated
macrophages may kill tumors by mechanisms
similar to those used to kill microbes

40. Cell mediated and humoral mechanisms (page 313) (see indicated page for further readings)
41. Immunosuppresed patient have increased risk of having cancer (page 313)
Persons with congenital immunodeficiencies develop cancers at about 200 times the rate in
immunocompetent individuals. Immunosuppressed transplant recipients and persons with AIDS
also have an increased incidence of malignancies. Most (but not all) of these neoplasms are
aggressive lymphomas composed of mature B cells. Particularly illustrative is the rare X-linked
recessive immunodeficiency disorder termed XLP (X-linked lymphoproliferative syndrome),
caused by mutations in the gene encoding an adapter protein, SAP, which participates in NK and
T-cell signaling pathways. In affected boys, EBV infection does not take the usual self-limited
form of infectious mononucleosis but instead evolves into a chronic or sometimes fatal form of
infectious mononucleosis or, even worse, a lymphoma comprised of EBV-infected B cells. Most
cancers occur in persons who do not suffer from any overt immunodeficiency. It is evident, then,
that tumor cells must develop mechanisms to escape or evade the immune system in
immunocompetent hosts. Several such mechanisms may be operative.

43.Genomic Instability (314)

Where DNA become vulnerable for mutations (irreversible)

Inherited defects in DNA repair genes allow mutations in other genes
DNA repair systems
 o Mismatch - can cause:
 HHPCC – microsatellite instability
 Nucleotide excision repair
 Xeroderma pigmentosa (AR) – sensitive to uv light
 Recombination repair
o Bloom, etc – hypersensitivity to DNA damaging agents
o BRCA 1 &BRCA 2 breast cancer
>> Genonic instability occurs when both DNA repair genes are lost
>> Microsatellite instability- tandems are shorter or longer
>>UV radiation causes cross-linkage of pyrimidine residues that now
cannot be excised
44. DNA Repair in maintaining integrity of genome

The importance of DNA repair in maintaining the integrity of the genome is further highlighted
by several inherited disorders in which genes that encode proteins involved in DNA repair are
defective. Individuals born with such inherited defects in DNA repair proteins are at a greatly
increased risk of developing cancer. Moreover, defects in repair mechanisms are present in
certain kinds of sporadic human cancers. Mutations in DNA-repair genes themselves are not
oncogenic, but their abnormalities greatly enhance the occurrence of mutations in other genes
during the process of normal cell division. Typically, genomic instability occurs when both copies
of the DNA repair gene are lost; however, some work has suggested that haploinsufficiency of at
least a subset of these genes may also promote cancer. As explained below, defects in three
types of DNA-repair systems—mismatch repair, nucleotide excision repair, and recombination
repair—contribute to different types of cancers.