The immune response to foreign antigens consists of

Humoral mechanisms (eg, antibodies)

Cellular mechanisms

Most humoral responses cannot prevent tumor growth. However, effector cells, such as T cells,
macrophages, and natural killer cells, have relatively effective tumoricidal abilities. Effector cell
activity is induced by cells that present tumor-specific antigens (TSAs) or tumor-associated
antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and is supported
by cytokines (eg, interleukins, interferons). Despite the activity of effector cells, host
immunoreactivity may fail to control tumor occurrence and growth.

Cellular Immunity
The T cell is the primary cell responsible for direct recognition and killing of tumor cells. T cells
carry out immunologic surveillance, then proliferate and destroy newly transformed tumor cells
after recognizing TAAs. The T-cell response to tumors is modulated by other cells of the immune
system; some cells require the presence of humoral antibodies directed against the tumor cells
(antibody-dependent cellular cytotoxicity) to initiate the interactions that lead to the death of
tumor cells. In contrast, suppressor T cells inhibit the immune response against tumors.
Cytotoxic T lymphocytes (CTLs) recognize antigens on target cells and lyse these cells. These
antigens may be cell surface proteins or may be intracellular proteins (eg, TAAs) that are
expressed on the surface in combination with class I major histocompatibility complex (MHC)
molecules. Tumor-specific CTLs have been found with neuroblastomas; malignant melanomas;
sarcomas; and carcinomas of the colon, breast, cervix, endometrium, ovary, testis, nasopharynx,
and kidney.
Natural killer (NK) cells are another population of effector cells with tumoricidal activity. In
contrast to CTLs, NK cells lack the receptor for antigen detection but can still recognize normal
cells infected with viruses or tumor cells. Their tumoricidal activity is termed natural because it
is not induced by a specific antigen. The mechanism by which NK cells discriminate between
normal and abnormal cells is under study. Evidence suggests that class I MHC molecules on the
surface of normal cells inhibit NK cells and prevent lysis. Thus, the decreased level of class I
molecule expression characteristic of many tumor cells may allow activation of NK cells and
subsequent tumor lysis.
Macrophages can kill specific tumor cells when activated by a combination of factors, including
lymphokines (soluble factors produced by T cells) and interferon. They are less effective than Tcellmediated cytotoxic mechanisms. Under certain circumstances, macrophages may present

TAAs to T cells and stimulate tumor-specific immune response. There are at least 2 classes of
tumor-associated macrophages (TAM):

TAM-1 (M1) cells facilitate T cell killing of tumors

TAM-2 (M2) cells promote tumor tolerance

Dendritic cells are dedicated antigen-presenting cells present in barrier tissues (eg, skin, lymph
nodes). They play a central role in initiation of tumor-specific immune response. These cells take
up tumor-associated proteins, process them, and present TAAs to T cells to stimulate the CTL
response against tumor. Several classes of dendritic cells can mediate tumor promotion or
suppression.
Lymphokines produced by immune cells stimulate growth or induce activities of other immune
cells. Such lymphokines include IL-2, also known as T-cell growth factor, and the interferons.
IL-12 is produced by dendritic cells and specifically induces CTLs, thereby enhancing antitumor
immune responses.
Regulatory T cells are normally present in the body and help prevent autoimmune reactions.
They are produced during the active phase of immune responses to pathogens and limit the
strong immune response that could damage the host. Accumulation of these cells in cancers
inhibits antitumor immune responses.
Myeloid-derived suppressor cells consist of immature myeloid cells and their precursors. These
cells accumulate in large numbers in cancers and potently suppress immune responses.

Humoral Immunity
In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant
protection against tumor growth. Most antibodies cannot recognize TAAs. Regardless, humoral
antibodies that react with tumor cells in vitro have been detected in the sera of patients with
various tumors, including Burkitt lymphoma; malignant melanoma; osteosarcoma;
neuroblastoma; and carcinomas of the lung, breast, and GI tract.
Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can
exert anti-tumor effects through complement fixation or by serving as a flag for destruction of
tumor cells by T cells (antibody-dependent cell-mediated cytotoxicity). Another population of
humoral antibodies, called enhancing antibodies (blocking antibodies), may actually favor rather
than inhibit tumor growth. The mechanisms and relative importance of such immunologic
enhancement are not well understood.

Failure of Host Defenses

Although many tumors are eliminated by the immune system (and thus are never detected),
others continue to grow despite the presence of TAAs. Several mechanisms have been proposed
to explain this deficient host response to the TAA, including the following:

Specific immunologic tolerance to TAAs in a process that involves antigen-presenting

cells and suppressor T cells, possibly secondary to prenatal exposure to the antigen

Suppression of immune response by chemical, physical, or viral agents (eg, helper T-cell
destruction by HIV)

Suppression of the immune response by cytotoxic drugs or radiation

Suppression of the immune response by the tumor itself through various complex and
largely uncharacterized mechanisms that cause various problems including decreased T,
B, and antigen-presenting cell function, decreased IL-2 production, and increased
circulating soluble IL-2 receptors (which bind and hence inactivate IL-2)

Presence and activity of TAM-2 (M2) cells, promoting tumor tolerance

What is angiogenesis?
Angiogenesis is the formation of new blood vessels. This process involves the migration, growth,
and differentiation of endothelial cells, which line the inside wall of blood vessels.
The process of angiogenesis is controlled by chemical signals in the body. These signals can
stimulate both the repair of damaged blood vessels and the formation of new blood vessels.
Other chemical signals, called angiogenesis inhibitors, interfere with blood vessel formation.
Normally, the stimulating and inhibiting effects of these chemical signals are balanced so that
blood vessels form only when and where they are needed.

Why is angiogenesis important in cancer?

Angiogenesis plays a critical role in the growth and spread of cancer. A blood supply is necessary
for tumors to grow beyond a few millimeters in size. Tumors can cause this blood supply to form
by giving off chemical signals that stimulate angiogenesis. Tumors can also stimulate nearby
normal cells to produce angiogenesis signaling molecules. The resulting new blood vessels
feed growing tumors with oxygen and nutrients, allowing the cancer cells to invade nearby
tissue, to move throughout the body, and to form new colonies of cancer cells, called metastases.
Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists
are trying to find ways to block tumor angiogenesis. They are studying natural and synthetic

angiogenesis inhibitors, also called antiangiogenic agents, with the idea that these molecules will
prevent or slow the growth of cancer.

How do angiogenesis inhibitors work?

Angiogenesis requires the binding of signaling molecules, such as vascular endothelial growth
factor (VEGF), to receptors on the surface of normal endothelial cells. When VEGF and other
endothelial growth factors bind to their receptors on endothelial cells, signals within these cells
are initiated that promote the growth and survival of new blood vessels.
Angiogenesis inhibitors interfere with various steps in this process. For example, bevacizumab
(Avastin) is a monoclonal antibody that specifically recognizes and binds to VEGF (1). When
VEGF is attached to bevacizumab, it is unable to activate the VEGF receptor. Other angiogenesis
inhibitors, including sorafenib and sunitinib, bind to receptors on the surface of endothelial cells
or to other proteins in the downstream signaling pathways, blocking their activities (2).

Are any angiogenesis inhibitors currently being used to treat

cancer in humans?
Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to be used alone
for glioblastoma that has not improved with other treatments and to be used in combination with
other drugs to treat metastatic colorectal cancer, some non-small cell lung cancers, and
metastatic renal cell cancer. Bevacizumab was the first angiogenesis inhibitor that was shown to
slow tumor growth and, more important, to extend the lives of patients with some cancers.
The FDA has approved other drugs that have antiangiogenic activity, including sorafenib
(Nexavar), sunitinib (Sutent), pazopanib (Votrient), and everolimus (Afinitor). Sorafenib
is approved for hepatocellular carcinoma and kidney cancer, sunitinib and everolimus for both
kidney cancer and neuroendocrine tumors, and pazopanib for kidney cancer. Researchers are
exploring the use of angiogenesis inhibitors to treat other types of cancer. In addition,
angiogenesis inhibitors are being used to treat some diseases that involve the development of
abnormal blood vessel growth in noncancer conditions, such as macular degeneration.

How are angiogenesis inhibitors different from conventional

anticancer drugs?
Angiogenesis inhibitors are unique cancer-fighting agents because they tend to inhibit the growth
of blood vessels rather than tumor cells. In some cancers, angiogenesis inhibitors are most
effective when combined with additional therapies, especially chemotherapy. It has been

hypothesized that these drugs help normalize the blood vessels that supply the tumor, facilitating
the delivery of other anticancer agents, but this possibility is still being investigated.
Angiogenesis inhibitor therapy does not necessarily kill tumors but instead may prevent tumors
from growing. Therefore, this type of therapy may need to be administered over a long period.

Do angiogenesis inhibitors have side effects?

Initially, it was thought that angiogenesis inhibitors would have mild side effects, but more
recent studies have revealed the potential for complications that reflect the importance of
angiogenesis in many normal body processes, such as wound healing, heart and kidney function,
fetal development, and reproduction. Side effects of treatment with angiogenesis inhibitors can
include problems with bleeding, clots in the arteries (with resultant stroke or heart attack),
hypertension, and protein in the urine (35). Gastrointestinal perforation and fistulas also appear
to be rare side effects of some angiogenesis inhibitors. Animal studies have revealed the potential
for birth defects, although there is no clinical evidence for such effects in humans.
It is likely that some of the possible complications of angiogenesis inhibitor therapy remain
unknown. As more patients are treated with these agents, doctors will learn more about possible
rare side effects.

Metastasis is the spread of a cancer or other disease from one organ or part of the body to
another without being directly connected with it. The new occurrences of disease thus generated
are referred to as metastases (mets).[1][2]

Steps of metastasis
The steps of metastasis include:

separation from the primary tumor

invasion through tissues around the initial lesion and penetration of their basement
membranes

entry into the blood vessels and survival within blood - spread via blood vessels is called
hematogenous spread

entry into lymphatics or peritoneal cavity - spread via lymph channels is called lymphatic
spread

reaching the distant organ like lungs, liver, brain bone etc.

formation of a new lesion along with new blood vessels feeding the tumor - formation of
new blood vessels is termed angiogenesis

All this while, the cancer cells have to avoid being killed by the bodys natural immune system.

Routes of metastasis
There are four possible routes of spread of cancer. These include:

spread via lymphatic channels this is favoured by most carcinomas

spread via blood vessels this is favoured by sarcomas and some carcinomas that
originate in the kidneys - because of their thinner walls veins are more frequently invaded
than arteries and the spread is via veins

spread via body cavities the cancer cells seed onto peritoneal (covering the gut and
stomach and other abdominal organs), pleural (covering the lungs), pericardial (covering
the heart) or subarchnoid spaces (covering the brain) and membranes

transplantation of the cancer this occurs by carriage of fragments of tumor cells via
needles or surgical instruments to other parts of the body during surgery and diagnostic
procedures

Why is metastasis dangerous?

Metastasis is of great importance since most of the cancer deaths are caused by spread of the
primary cancer to distant sites. In most cases, cancer patients with localized tumors have a better
chance at survival than those with metastatic tumors.
New evidence shows that 60% to 70% of patients have initiated the metastatic process by the
time of diagnosis. In addition, even patients that have no evidence of tumor spread at diagnosis
are at risk for metastatic disease and need to be treated accordingly.

Metastasis seed and soil theory and organs susceptible

Metastasis is one of three hallmarks of malignancy or cancer as opposed to a benign tumor. Most
tumors and other neoplasms can metastasize. The degree of ability to spread, however, varies
between different types of tumors. For example, basal cell carcinoma rarely spreads.
Some organs are more prone than others to metastasis of primary tumors. This was first
discussed as the "seed and soil" theory by Stephen Paget over a century ago in 1889. For
example, bones are the favoured site for prostate cancer, colon cancer spreads to liver, stomach
cancer can metastasize to the ovaries and is then called Krukenberg tumor.

The theory states that cancer cells find survival outside their primary suites difficult. To spread
they need to find a location with similar characteristics. For example, breast cancer cells need
calcium ions from breast milk to proliferate. Thus they may prefer the bones as a site of spread as
bones are rich in calcium. Malignant melanoma favors melanocytes and nerves and thus may
spread to the brain since the neural tissue and melanocytes arise from the same cell line in the
embryo.