Lymphatic system and spread of

cancer
Oncology UM
 Intro / Purpose
 A type vascular system that works with the side
of the circulatory system to help keep the body in
a state of homeostasis
 A network of nodes that act as tiny filters to
strain out invading organisms
 Helps fight disease and build immunity
 Produces various types of WBC
 Makes antibodies
 Drains excess fluids & protein to avoid episodes
of edema
 Functions
• Absorbs & transfers fats and fat-soluble
vitamins from the digestive system to cells
• Return waste and extra fluids from circulatory
system
• Important to the body’s immune system
Active immunity results when exposure to a disease organism triggers the immune system
to produce antibodies to that disease. Exposure to the disease organism can occur through
infection with the actual disease (resulting in natural immunity), or introduction of a killed
or weakened form of the disease organism through vaccination (vaccine-induced
immunity). Either way, if an immune person comes into contact with that disease in the
future, their immune system will recognize it and immediately produce the antibodies
needed to fight it.
Active immunity is long-lasting, and sometimes life-long.

Passive immunity is provided when a person is given antibodies to a disease rather than
producing them through his or her own immune system.
A newborn baby acquires passive immunity from its mother through the placenta. A
person can also get passive immunity through antibody-containing blood products such
as immune globulin, which may be given when immediate protection from a specific
disease is needed. This is the major advantage to passive immunity; protection is
immediate, whereas active immunity takes time (usually several weeks) to develop.
However, passive immunity lasts only for a few weeks or months. Only active immunity is
long-lasting.
 Formation & Flow of Lymph

• Fluid & proteins escaping from

vascular capillaries is collected by
lymphatic capillaries & returned to
the blood
• Respiratory & muscular pumps
promote flow of lymphatic fluid
• Lymphatic vessels empty into
subclavian veins
 Lymphatic Vessels & Circulation
• Capillaries that begin as
closed-ended tubes found
in spaces between cells
• Combine to form lymphatic
vessels
– resemble veins with thin
walls & more valves
• Fluid flows through lymph
nodes towards large veins
above the heart
– lymph emptied into bloodstream
 Lymphatic System

• Organs, vessels and a fluid called

lymph
– similar to interstitial fluid
• Organs involved
– red bone marrow
– thymus
– spleen
– lymph nodes
– diffuse lymphatic tissue
• tonsils, adenoids & peyers
patches
 Major Structures
• Lymph fluid
• Lymph vessels
• Lymph nodes
• Tonsils & Adenoids
• Veriform appendix & peyer’s patches
• Spleen
• Thymus
• Lymphocytes
 Lymph Fluid
• Referred to as Lymph
• Intercellular fluid
– Plasma around capillaries into spaces between
cells. Carries food, oxygen, & hormones to cells
– remove cellular waste products, pathogens, and
dead cells
– Must be filtered before reentering the circulatory
system by the lymph nodes
 Lymphatic Vessels
• Lymph capillaries – thin walled tubes under
the skin that carry lymph
• Lacteals – lymph capillaries located in the villi
that line the walls of the small intestine
– Fats and vitamins are absorbed
• Lymphatic duct – returns lymph back to the
bloodstream
 Lymphocytes
 Types of WBC that invade and digest unwanted organisms that
could harm the body
 When fighting infections, nodes can become swollen and tender to
touch
◦ B-Cells produce and secrete antibodies
◦ T-Cells mature in the thymus contribute to the immune system
 Interferon proteins that fight viruses by stopping multiplying cells
 Lymphokines – attract macrophages and prepare infected site for a fight
 Macrophage – interact with other cells of immune system by eating invading cells
 Phagocyte – large WBC that can eat and destroy pathogens

 Phagocytosis – the PROCESS by which phagocytes eat and

destroy pathogenic substances
 The pus that occurs from an infected site is old dead WBCs
 Lymph Nodes
 Small bean shaped structures in the lymph
vessels
 Filters harmful substances before lymph is
returned to the circulatory system
 Examples of harmful substances
◦ Bacteria
◦ Viruses
◦ Malignant cells

 Enlargement of nodes can indicate disease

 Location of Lymph Nodes
• Cervical
• Axillary
• Abdominal
• Inguinal
• Popliteal
• Also located
throughout the
thoracic cavity
 Tonsils
 Mass of lymph tissue that
form a protective ring
around the nose and upper
throat
◦ Adenoids – located:
 nasopharynx
◦ Palatine tonsils – located:
 On right & left side of the throat
 Can be seen through the mouth
- Lingual – located:
- Base of tongue (lingual means
tongue)
 Spleen
 Filters microorganisms &
foreign material from blood
 Destroys old RBC
 Hemolytic (hem means blood – lytic
means destroy)
 Stores extra erythrocytes to
maintain balance of RBC &
plasma
 Forms lymphocytes &
monocytes
◦ Specialized in WBC
 Plays a role in immune system
Thymus
• Plays role in the immune
and endocrine system
• Located superior to the
heart made of lymphatic
tissue
– Reaches development during
puberty
Veriform Appendix & Peyer’s Patches
• Lymphatic structures or tissues located in
the digestive system
• Protect against invaders that enter into t
he digestive system.
 The Immune System
• Protect the body from harmful substances
– Pathogens
– Allergens
– Toxin
– Malignant cells
 The Body Defense Systems
 Skin
◦ Protective barrier prevents pathogens from entering the
body
 Respiratory
◦ Nose hairs & mucous membrane to slow pathogens form
entering the nose
 Coughing & sneezing
 Digestive
◦ Acids and enzymes in the stomach to fight pathogens that
enter in foods
 Lymphatic
◦ Filters and destroys pathogens
 Immune Reaction
• Antigen-Antibody Reaction
– Antigen a substance that the body thinks if foreign
• Viruses, bacteria, toxins, & transplanted tissues

– Antibody a disease fighting protein created in the

immune system to response to specific antibodies
 Immune Response
 Phagocytes – from WBC that circulate the body
and ingest diseased and dead cells
 Lymphocytes formed in bone marrow as stem
cells – WBC that act like an antibodies
◦ B cells – lymphocytes that produce antibodies capable
of coding to confront antigen for destruction
◦ T cells – small lymphocytes that mature in the thymus,
contribute to defense by coordinating immune
defenses and killing infected cells on contact
 Factors that influence an immune
response
 Health
◦ Better health immune system can respond better
 Age
◦ Older tend to have more acquired immunity
 Heredity
◦ Genes and genetic disorders that shape the makeup of
antibodies
 Opportunistic infection
◦ A nonpathogen turned pathogen when host is in a
weaken state
 Allergic reaction
• When the body’s immune system reacts to a
harmless allergen like pollen
– Allergen is an antigen capable of inducing an
allergic response
• Localized reaction – occurs in area of contact with
allergen such as poison ivy
• Systemic reaction – affects different body systems at
one time; anaphylaxis
 Immunity
being resistant to a specific disease

• Natural passed from mother to child

• Acquired or active obtained by
development of antibodies during attack
of an infectious disease such as
chickenpox
• Artificial also known as acquired through
immunization or vaccination
 Oncology
 Study of prevention, causes, and treatment of tumors also
known as neoplasm and cancer
◦ Cancer represent over 200 forms of malignancies

Terms related to tumors

Neoplasm- abnormal tissue formation (neo –new & plasm –
formation)
Benign – type tumor that is nonmalignant and better chance of
recovery
Malignant – harmful tumors that spread
Metastasize - describes the process by which cancer is spread
primary – the original site of the neoplasm
secondary – spread to another site
What Is Cancer?
Cancer is the general name for a group of more than 100 diseases. Although there
are many kinds of cancer, all cancers start because abnormal cells grow out of
control. Untreated cancers can cause serious illness and death.
Normal cells in the body
The body is made up of trillions of living cells. Normal body cells grow, divide, and
die in an orderly fashion. During the early years of a person’s life, normal cells
divide faster to allow the person to grow. After the person becomes an adult,
most cells divide only to replace worn-out or dying cells or to repair injuries.
How cancer starts
Cancer starts when cells in a part of the body start to grow out of control. Cancer
cell growth is different from normal cell growth. Instead of dying, cancer cells
continue to grow and form new, abnormal cells. Cancer cells can also invade
(grow into) other tissues, something that normal cells cannot do. Growing out
of control and invading other tissues are what makes a cell a cancer cell.
Cells become cancer cells because of DNA (deoxyribonucleic acid) damage. DNA is in
every cell and it directs all the cell’s actions. In a normal cell, when DNA gets damaged
the cell either repairs the damage or the cell dies. In cancer cells, the damaged DNA is
not repaired, and the cell doesn’t die like it should. Instead, the cell goes on making
new cells that the body doesn’t need. These new cells all have the same abnormal
DNA as the first cell does.

People can inherit abnormal DNA, but most DNA damage is caused by mistakes that
happen while the normal cell is reproducing or by something in the environment.
Sometimes the cause of the DNA damage may be something obvious like cigarette
smoking or sun exposure. But it’s rare to know exactly what caused any one person’s
cancer.

In most cases, the cancer cells form a tumor. Some cancers, like leukemia, rarely form
tumors. Instead, these cancer cells involve the blood and blood-forming organs and
circulate through other tissues where they grow.

How cancer spreads

Cancer cells often travel to other parts of the body where they begin to grow and form
new tumors. This happens when the cancer cells get into the body’s bloodstream or
lymph vessels. Over time, the tumors replace normal tissue. The process of cancer
spreading is called metastasis.
Routes of Metastasis
There are three primary ways tumors can spread to distant organs:
Through the circulatory (blood) system (hematogenous)
Through the lymphatic system
Through the body wall into the abdominal and chest cavities (transcoelomic).
The circulatory system is the primary route of spread to distant organs, while lymphatic
vessels provide a route to local lymph nodes, after which metastases often travel through
the blood. While the circulatory system appears to be the most common route, the extent
of lymphatic versus hematogenous spread appears to depend on the origin and location
of the primary tumor. For example, bone and soft tissue tumors (sarcomas) spread
primarily through the blood, while melanoma, breast, lung and gastrointestinal tumors
spread through the lymphatic system. Transcoelomic spread is fairly uncommon, and
appears to be restricted to mesotheliomas and ovarian carcinomas.
In order for tumor cells to gain access to lymphatic or blood vessels, tumors need to
promote the growth of these vessels into and around the tumor. Growth of blood vessels
is called angiogenesis, and growth of lymphatic vessels is lymphangiogenesis.
Spread of Cancer Through the Lymphatic System
The lymphatic system plays an important role in controlling the movement of fluid
throughout the body. Specifically the lymphatic system controls the flow of lymph, a
colorless fluid containing oxygen, proteins, sugar (glucose) and lymphocytes. There are
some similarities and differences between the circulatory system and the lymphatic
system. Small lymphatic vessels merge into larger ones and these large vessels
eventually empty into lymph nodes. Lymph nodes are kidney bean shaped tissues that
are found in grape-like clusters in several locations around the body. Lymph nodes are
sites of immune system activation and immune cell proliferation . The fluid in this
extensive network flows throughout the body, much like the blood supply. It is the
movement of cancer cells into the lymphatic system, specifically the lymph nodes, that
is used in the detection of metastatic disease. When a cancer cell has moved through
the blood or lymphatic systems or via direct contact to another location, it may divide
and form a tumor at the new site. The lymphatic system plays a crucial role in the
metastasis of certain cancers. Lymphatic vessels are designed for entry and exit of
immune cells, and are therefore easy for tumor cells to enter. In addition, the flow of
lymph is quite slow, so there is little stress to harm cells. Researchers originally
believed tumor cells invaded the lymphatic system by eroding the vessel walls as the
tumor advanced and metastasis would then occur by passive drainage.
However, current evidence suggests the interactions between
metastasizing cells and lymph vessels are much more active and
complex, and specific interactions between the two are required. The
presence of metastases in lymph nodes near the primary tumor often
indicates metastasis to distant organs, and is a significant prognostic
indicator in many cancers. To assess the presence of metastasis to
surrounding lymph nodes, physicians perform a lymph node biopsy. In
this procedure, the lymph nodes are removed by surgery and are
checked for the presence of cancer cells. Nodes are determined either
positive or negative for cancer. Because lymph drainage pathways from
a tumor vary greatly between patients, even for the same area, up to
30% of tumors cannot be accurately predicted to migrate to specific
lymph nodes. Improvement in lymphatic imaging and mapping are
needed to ensure that metastasizing cancers are not accidentally
missed.
Organ Targeting: Anatomic Model, Seed and Soil Model
The Anatomic Model
In the anatomic model of metastasis, secondary tumors occur in the organs which they
encounter first during their dissemination from the primary tumor. This scenario appears to
occur in regional metastases, where tumor cells gain access to nearby tissue or lymph nodes
through the blood or lymphatic circulation. For example, liver metastasis is a major occurrence
in patients with colorectal cancer. In this case, the capillary bed of the liver is the first
encountered by the tumor cells after leaving the colon, and the liver seems to provide a
suitable environment for the growth of these secondary tumors. However, metastasis to
distant organs occurs through a different mechanism.
The Seed and Soil Hypothesis
Early cancer researchers noticed a propensity for certain cancers to metastasize to the same
organ. In 1889 Stephen Paget observed that patients with breast cancer often developed
secondary tumors in the liver. He considered it unlikely that this occurrence was due primarily
to accessibility of the liver by the blood supply, as other organs receiving equivalent blood
supply rarely developed metastases. He instead developed the "Seed and Soil" hypothesis, in
which certain tumor cells (the seeds) can only successfully colonize selective organs (the soil)
that have suitable growth environments.
The current view of the Seed and Soil Hypothesis consists of three important concepts.
Primary tumors and their metastases consist of genetically diverse tumor and host cells.
Metastasis selects for cells that can succeed in all phases of the metastatic process. In essence,
a successful metastatic cell must be a decathalete: good in all the events, and not just one or
two.
Metastases generally develop in a site specific way. Because the microenvironments (the soil) of
each organ is different, individual cancer cells may be able to colonize one specific organ.
At the heart of the Seed and Soil hypothesis is the idea that successful metastasis depends on
the interaction of the metastasizing tumor cells with the cells of the target organ (the stroma, or
tumor microenvironment). Not only must tumor cells must be able to produce factors that alter
the stromal cells in such a way as to better serve the survival and growth of the tumor, but the
environment in which the cancer cell finds itself must be capable of responding to those
signals. If the cancer cell finds itself in an inhospitable soil (i.e. it cannot subvert the stroma to
serve its needs), successful metastsis will be impossible.
Recent studies examining the profile of genes expressed in tumors that metastasis to specific
organs have identified specific genetic signatures of these tumors. For example, genes that
mediate the metastasis of breast cancer to bone are different than those that mediate
metastasis to the lung. In essence, different sets of genes allow tumor cells to specifically
interact with the stromal cells of the target organ. These findings may lead to therapeutic
strategies to target the metastatic properties of tumors.
 Lymphatic vasculature in metastatic
tumour spread
• Current understanding of lymphatic biology is its
an active system regulated by a complex array of
lymphangiogenic factors, chemokines and
immune cell subsets.
• The lymphatic vasculature primarily functions to
regulate tissue fluid homeostasis, collect antigens
and other macromolecules from peripheral
tissues, and traffic immune cells such as antigen-
presenting dendritic cells from the periphery to
lymph nodes.
• invasive tumor cells can exploit the loose,
overlapping endothelial cell junctions and
incomplete basement membrane of lymphatic
capillaries to take advantage of the transport
network that is highly amenable to cell
survival. It has become apparent that
lymphangiogenesis, the generation of new
lymphatic vessels actively contributes to
tumor metastasis.
 Tumour Lymphangiogenesis
• Tumor-induced lymphangiogenesis is mediated
by lymphangiogenic growth factors that are
produced and secreted by the tumors
themselves, stromal cells, tumor-infiltrating
macrophages, or activated platelets.
• The overexpression of either VEGFC or VEGF-D in
tumors significantly increased tumor-associated
lymphatic vessel growth (primarily at the tumor
margin) and increased incidence of lymph node
metastasis
• Conversely, blockade of signaling via VEGFR-3 using either
soluble VEGFR-3 fusion proteins that act as a trap for VEGF-C
and -D, or neutralizing antibodies targeting VEGFR-3, reduced
tumor lymphangiogenesis and lymphatic metastasis.
• Transgenic mice overexpressing VEGF-A in the skin exhibited
enhanced tumo lymphangiogenesis and metastasis to lymph
nodes and beyond when subjected to a multistep chemical
skin carcinogenesis cancer model.
• Neuropilin-2, normally expressed in lymphatic vessels during
embryogenesis, has recently been found expressed in tumor
associated lymphatic vessels in both
• experimental mouse tumor models and human skin cancers.
Importantly, functional blockade of neuropilin-2 using a
neutralizing antibody blocked lymphatic endothelial cell
migration but not proliferation, reduced tumoral
lymphangiogenesis, and delayed metastasis to sentinel lymph
nodes.
Christiansen and Detmar,Genes & Cancer
2011(2);1146-1158
 Role of chemokines in invasion of
lymphatics by tumour cells
• One of the key physiological roles of the lymphatic
vasculature is the trafficking of immune cells from
peripheral tissues to lymph nodes, where adaptive
immune responses are instigated. This process is
actively regulated and controlled by a family of
secreted proteins called chemokines. Under normal
physiological conditions, chemokines are critical to the
coordinated homing of hematopoietic cells to specific
sites and tissues. Tumor cells, through the expression
of chemokine receptors, exploit this established
lymphatic trafficking system to mediate both invasion
into the lymphatic vasculature and beyond to form
metastases in lymph nodes and distal tissues.
 CXCR4 and CXCL12
• The initial identification of the chemokine
receptors CXCR4 and CCR7 on human breast
cancer cells and the expression of their respective
ligands (CXCL12 [SDF-1] and CCL21) in organs that
tumors normally metastasize to have led to a
rapid expansion in the field of chemotactic tumor
metastasis.
• CXCR4 and its ligand CXCL12 are widely expressed
in normal tissues and play fundamental roles in
fetal development, mobilization of hematopoietic
stem cells, and trafficking of lymphocytes.
• Importantly, CXCR4 is largely absent from normal breast,
prostate, or ovarian epithelia; however, it is
characteristically expressed on malignant epithelial cells
isolated from these tissues.
• Malignant cells that express functional CXCR4 exhibit
directed metastasis into tissues that express CXCL12. A high
concentration of CXCL12 in the lymph nodes and the
ensuing gradient this creates within lymphatic vessels
strongly attract tumor cells, resulting in increased
metastases to the node. Tumor associated lymphatic
vessels, but not normal lymphatic vessels highly express
CXCL12,highlighting an active role for the tumor associated
lymphatic endothelium in metastatic tumor spread.
• Evidence suggests that dissemination of
metastases to distal organs beyond the
draining lymph node is also governed by a
CXCL12 gradient. Indeed, tissues that highly
express CXCL12, such as the lung, liver, and
bone, are preferential sites for metastasis.
 CCR7 and its ligand CCL19 and CCL21
• The chemokines CCL19 and CCL21 are also key players
in the active metastatic dissemination of malignant
cells via the lymphatic system. These chemokines are
the only known ligands for the chemokine receptor
CCR7 and under physiological conditions regulate the
trafficking of CCR7-positive T and lymphocytes and
antigen-presenting dendritic cells to lymph nodes.
• CCR7 expression on tissue sections of cervical,
colorectal, gastric, mammary, esophageal, lung, and
prostate carcinomas has been correlated with
metastasis to lymph nodes.
• Using experimental models, CCR7-positive tumor cells have
demonstrated chemotactic migration towards CCL21-producing
lymphatic endothelial cells and metastasis to tumor-draining lymph
nodes. Moreover, blockade of CCL21 using a soluble inhibitor was
also shown to inhibit metastatic migration in vivo.
• In addition to sensing chemotactic gradients established by
lymphatic endothelial cells, tumor cells may also set up autologous
gradients via secretion of CCL19 and CCL21 into the extracellular
matrix. This secretion in the presence of slow interstitial flow may
preferentially guide tumor cells towards more, rather than less,
functional lymphatic vessels. The biophysical properties of the
lymphatic microenvironment are therefore linked with the active
chemotactic migration of tumor cells into the lymphatic
vasculature, highlighting the dynamic processes that regulate
lymphatic metastasis.
• Increased lymphatic flow was reported to upregulate CCL21
expression by both the lymphatic endothelium125 and also the
lymph node paracortex, primarily by T cell zone fibroblastic reticular
cells, and thereby may further enhance the migration of metastatic
cells into the lymphatics. Flow-mediated upregulation of CCL21
increased transmigration of dendritic cells, suggesting flow-
regulated chemotactic enhancement may also be important for the
active migration of CCR7-positive metastatic cells into the
lymphatics.
• Active metastatic spread to the lymphatic vasculature may be
further enhanced by a recently identified cross-talk mechanism that
links VEGF-C and CCL21. Tumor cell expression of both VEGF-C and
CCR7 was found to synergistically promote tumor invasion into the
lymphatics, primarily mediated by VEGF-C–induced increases in
lymphatic endothelial cell expression of CCL21.
Christiansen and Detmar,Genes & Cancer
2011(2);1146-1158
 Lymphangiogenesis and tumour
immunity
• The host immune system recognizes and interacts with
tumors and can be dramatically affected by molecules
that originate from within the tumor
microenvironment.
• Emerging evidence suggests that this niche may not
only be structurally more amenable to the arrival of
tumor cells but that these changes may also influence
the immunological phenotype both within the node
and in the peritumoral region where new lymphatic
structures are formed. Indeed, tumor derived factor
can influence both innate and antigen-specific immune
functions.
• Multiple mechanisms may act to suppress tumor-specific immune
responses in patients, including increased intratumoral and
circulating suppressor cell populations such as myeloid-derived
suppressor cells and T regulatory lymphocytes, polarization of the
cytokine milieu from a cytotoxic Th1 to an immunosuppressed Th2
phenotype, diminished presentation of tumor-derived antigens,
and the outgrowth of poorly immunogenic tumor cell populations.
• The sentinel lymph node, being the direct drainage site for the
tumor, is strongly influenced by tumor-derived factors. Sentinel
lymph nodes are also the point of contact for tumor-derived
antigens and immune cells and are therefore extensively studied for
detection of early immunological changes that may facilitate tumor
progression.
• Among these potentially immunomodulatory factors are the
lymphangiogenic growth factors VEGF-A and VEGF-C and the
chemotactic ligand CCL21.
 VEGF-Mediated Modulation
of Leukocytes
• VEGFs may impact tumor-immune surveillance via modulation of
dendritic cell maturation and recruitment. Host professional
antigen-presenting cells such as dendritic cells are key to tumor
specific immune responses. Dendritic cells sample and present
tumor-derived antigens to naive T cells via major histocompatibility
complex (MHC) class I or class II molecules and thereby initiate
antigen-specific antitumor-immune responses. Inadequate
presentation of tumor antigens by dendritic cells is therefore one
potential mechanism by which tumors escape from the host
immune system. Tumor-produced VEGF-A can directly modulate
dendritic cell differentiation.
• Tumor-expressed VEGF-C has also been suggested to impact
dendritic cell infiltration into gastric carcinoma. Increased VEGF-C
expression negatively correlated with the degree of dendritic cell
infiltrate into the tumor, suggesting that VEGF-C may negatively
impact the recruitment of dendritic cells.
• VEGFs have been shown to modulate T cell proliferation, phenotype, and activity.
Indeed, small interfering RNA mediated downregulation of VEGF-C in a mouse
mammary tumor model has been shown to not only decrease tumoral
lymphangiogenesis but also to impact tumor-infiltrating lymphocytes.
• In vitro proliferation assays using circulating T cells from both ovarian cancer
patients and healthy donors demonstrated that VEGF-A directly inhibited T
lymphocyte proliferation.
• VEGF-A also significantly reduced the cytotoxic activity of T cells. These data are
supported by findings that VEGF-A can polarize peripheral blood lymphocytes from
a Th1 to a Th2 phenotype. Th1 cells are characterized by their ability to secrete the
proinflammatory cytokine IFN-γ that is key to the survival, proliferation, and
effector function of cytotoxic T cells. Polarization to the potentially
immunosuppressive IL-4–secreting Th2 phenotype can have a significant impact
upon the generation of effective cytotoxic T cell antitumor immunity and thereby
provide a permissive environment for tumor progression and metastasis.
• VEGF-A can also modulate T cell activity, specifically via direct inhibition of
proliferation. VEGF-A has also been implicated in the induction and maintenance
of T regulatory cells.
• Natural killer (NK) cells are a key cell subset
involved in innate antitumor immunity.
Interestingly, a recent study has identified VEGF-C
as a key regulator of NK cell cytotoxicity and
highlighted a critical role for this regulation in
mediating immune tolerance. Noncytotoxic
uterine NK cells were found to express
significantly higher levels of VEGF-C when
compared to their cytotoxic NK cell counterparts
(both peripheral and uterine), which retained
their cytotoxic activity.
Christiansen and Detmar,Genes & Cancer
2011(2);1146-1158
 Figure 3. Hypothetical model for lymphatic-associated modulation of
antitumor immunity. Tumor-derived VEGFs induce lymphangiogenesis,
increasing the peritumoral lymphatic vasculature and the lymphatic
vasculature within tumor-draining lymph nodes
• The increased tumor-associated lymphatic structures may
express elevated levels of CCL21, the upregulation of which
may be induced either directly by VEGF-C or as a result of
the increased lymphatic flow rates observed within tumor-
associated lymphatics (A)
• VEGF-A and -C expressed within the tumor
microenvironment may reduce the numbers of mature
dendritic cells and thereby reduce tumor-derived antigen
presentation to T lymphocytes and therefore
adaptiveantitumor cytotoxicity (B). Innate immunity may
also be affected as VEGF-C may protect tumor cells from NK
cell–mediated killing. Increased CCL21 expression by
tumor-associated lymphatic endothelial cells may recruit
lymphoid tissue inducer (LTi) cells (B).
• Resulting tertiary lymphoid structures may provide a niche for the
differentiation of functional suppressive T regulatory (Treg) cell
populations and may recruit other suppressive cells such as
myeloid-derived suppressor cells (MDSC) (C). Adaptive immunity
may be further impacted with clonal deletion of potentially tumor-
reactive T cells following antigen presentation directly by lymphatic
endothelial cells (C). Elevated tumor-associated VEGF and CCL21
expression may also induce a toleragenic cytokine milieu
characterized by increased expression of TGF-β and IL-10 (C). These
immunological alterations may act to enhance tumor metastasis to
the draining lymph nodes, whereby similar chemokine and
lymphangiogenic factor expression gradients may facilitate
metastasis to distal organs (C).
 Conclusion
• Increasing evidence from both experimental murine
tumor model systems and clinical data indicates that
tumor-associated lymphangiogenesis promotes
metastasis and that this has prognostic importance for
patients. It is now emerging that the processes that
regulate lymphatic metastasis are significantly more
complex than those originally proposed. It is emerging
that lymphatic metastasis involves intricate regulation
by multiple soluble factors and cell types that not only
drive the active migration of tumor cells into lymphatic
vessels and beyond but may also act to regulate the
balance between host immunity and tolerance.