That is, the ECM is one of the environmental factors (along with hormones) that communicate with a cell nucleus, modifying nuclear structures and leading to selective gene expression. Bissell's theory implied that alterations in the ECM or cellular responses to it could lead to malignancy, a radical idea at the time.
Bissell was among the first to connect the regulation of cell growth and development with the cell's environment.
Scientific Impact: The ECM theory has steadily gained scientific acceptance and yielded a growing volume of knowledge about both normal and cancer cells. Bissell's work has greatly influenced cell biology, a field in which cells are studied as living entities that take on specialized functions, organize into communities, and interact with their environment.
The Seed and Soil Hypothesis
Very early evidence for the importance of the stroma in tumor development came from
Stephen Paget who, in 1889, observed that breast cancer patients primarily developed
secondary tumors in the liver. If tumor metastasis depended only on accessing distant
organs through the blood supply, then other tissues should have been equally affected.
Paget thus developed the Seed and Soil hypothesis, in which given tumor cells (seeds)
can only colonize particular distant tissues (soil) that had a suitable growth environment.
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In the intervening years, Paget's observation's have been verified with
other cancers; prostate cancers
generally metastasize to the bone,
sarcomas to the lung.
Recent evidence suggests that
oncogenes and tumor suppressor
genes, classes of genes essential for
the initiation of tumors, do not play a
major role in development of
metastasis. Instead, the stroma
appears to be a far more critical
regulator of metastasis. |
Two key events must occur for site-specific metastasis to occur:
- First, a viable landing spot (pre-metastatic niche) in the target organ must be
formed to allow the tumor to survive in an otherwise unwelcoming environment.
- Second, the invading tumor cells must express appropriate genes to allow them to
colonize the niche.
The fact that millions of tumor cells may be shed into the circulation each day, but only a
few ever succeed in colonizing another tissue, highlights the extreme inefficiency of
metastasis, and suggests that normal tissues are hostile to invading cells. Cancer cells that are shed into the circulatory system but do not take hold and begin to grow are
termed dormant.
The current view of the Seed and Soil Hypothesis consists of three important
concepts:
1) Primary tumors and their metastases consist of genetically diverse tumor and host
cells.
2) Metastasis selects for cells that can succeed in all phases of the metastatic process. In
essence, a successful metastatic cell must be a decathlete: good in all the events, and
not just one or two.
3) Metastases generally develop in a site-specific way. Because the microenvironments
(the soil) of each organ are different, individual cancer cells may be able to colonize one
specific organ.
Recent studies examining the profile of genes expressed in tumors that metastasize to
specific organs have identified specific genetic signatures of these tumors.
CISN Summary
- A tumor can change its microenvironment, and the microenvironment can affect
how a tumor grows and spreads.
- A person's phenotype (environment inside or outside the body) can override
a normal genotype (DNA) and cause cancer.
- Cancer Corrupts Surrounding Tissue
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This picture illustrates that,
in addition to all of the
molecular changes that
occur within a cancer cell,
the environment around the
tumor changes dramatically
as well.
The cancer cell loses
receptors that would
normally respond to
neighboring cells that call
for growth to stop. Instead,
tumors amplify their own
supply of growth signals. They also flood their neighbors with other signals called
cytokines and enzymes called proteases. |
Image courtesy of the National Cancer Institute |
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This action destroys both the basement membrane and surrounding matrix, which lies
between the tumor and its path to metastasis--a blood vessel or duct of the lymphatic
system.
This allows metastatic cells to enter the bloodstream, which transports the cells to new
sites where they can set up shop and begin a new cycle of growth and invasion.