The Tumor Microenvironment:
What’s Going On in the Neighborhood?

A tumor's microenvironment consists of normal cells, molecules, hormones and blood vessels that feed the tumor cell. By sending out chemical signals, tumors can change their microenvironment and the microenvironment can change the tumor. This communication (often called cross-talk) between a tumor and its surroundings is very important.

Within the past several years, it has become evident that the tumor microenvironment plays an important role in both tumor initiation and progression. Due to this new knowledge, researchers have begun to investigate treatments that target both the cancer and its surroundings.

Systems biology research helps us to understand the underlying structure of cell signaling networks and how changes in these networks may affect the transmission and flow of information.

The Extracellular Matrix (ECM)

ECM is a network of proteins surrounding cells in the body and was long believed to function mainly as inert scaffolding for tissue. But in the early 1980s, Dr. Mina Bissell of Lawrence Berkeley National Laboratory proposed that the ECM is a key "signaling molecule" crucial for the normal functioning of cells.

Image Courtesy of Tirrell, M., E. Kokkoli and M. Biesalski, Surface Science, 500, 61 (2002)

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.

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

		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

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.