[ RadSafe ] Article: RADIATION AND THE MICROENVIRONMENT – TUMORIGENESIS AND THERAPY

[John Jacobus]

This appeared in Nature Reviews Cancer 5, 867-875
(2005)  

It is a long article [1081K], so I have only supplied
the first few paragraphs.  If you would like to see
the whole article, let me know, as this is an
education opportunity.

Mary Helen Barcellos-Hoff1, Catherine Park2 & Eric G.
Wright3   about the authors 

1 Life Sciences Division, Lawrence Berkeley National
Laboratory, 1 Cyclotron Road, Berkeley, California
94720, USA.
2 Department of Radiation Oncology, University of
California, San Francisco, San Francisco, California
94143, USA.
3 Department of Molecular and Cellular Pathology,
University of Dundee, Ninewells Hospital and Medical
School, Dundee DD19SY, Scotland, UK.

correspondence to: Mary Helen Barcellos-Hoff
mhbarcellos-hoff at lbl.gov 

Radiation rapidly and persistently alters the soluble
and insoluble components of the tissue
microenvironment. This affects the cell phenotype,
tissue composition and the physical interactions and
signalling between cells. These alterations in the
microenvironment can contribute to carcinogenesis and
alter the tissue response to anticancer therapy.
Examples of these responses and their implications are
discussed with a view to therapeutic intervention.

IONIZING RADIATION (IR) is both a carcinogen and a
therapeutic agent — low-dose exposure can increase an
individual's risk of developing cancer, but when given
at high doses it can slow or stop tumour growth (Box
1). How can IR have such a broad range of effects?
Studies into the cellular effects of IR have led
scientists to a detailed understanding of the cell
cycle, DNA damage, apoptosis and the molecular
machines that initiate and execute DNA repair. Cancer
radiotherapy relies on two essential components —
killing cancer cells while sparing normal tissues.
This is achieved in part by taking advantage of the
physical attributes of IR that, through sophisticated
planning and delivery techniques, make it possible to
safely increase the radiation dose to the tumour while
limiting the dose to surrounding normal tissues95.
Further therapeutic benefits can be accrued by
understanding and manipulating the biological response
of the microenvironment to IR to increase a tumour's
sensitivity to radiation or to inhibit deleterious
effects, respectively.

Many people assume that one must look no further than
IR-induced DNA damage to understand how it functions
as a carcinogen and can be used to kill cancer cells.
However, IR has many multicellular effects, indicating
that additional mechanisms might contribute to the
response to and consequences of IR exposure. In an
intact organism, all cells are subject to complex
regulatory mechanisms that depend on their
interactions with the cells and cellular products that
comprise their microenvironment. Therefore, the
effects of an agent such as IR should not just be
considered in terms of isolated cells, but rather that
the entire tissue has a role in determining the
response of any individual cell to any regulatory or
damaging signals.

When cells are exposed to IR, DNA damage induces a
stress response through activation or repression of
distinct target proteins that primarily function to
facilitate DNA repair and prevent the proliferation of
damaged cells. Similar to the stress response
programme within cells, IR induces multicellular
programmes that orchestrate a response to damage at
the tissue level1. Such programmes are executed by
soluble signals such as CYTOKINES, GROWTH FACTORS AND
CHEMOKINES, which function on the PARENCHYMA and
STROMA to modulate cell behaviours and phenotypes. IR
can elicit an 'activated' phenotype in some cells that
promotes rapid, persistent stromal remodelling of the
EXTRACELLULAR MATRIX (ECM). Remodelling of the ECM
occurs through the induction of proteases and growth
factors, and the chronic production of REACTIVE OXYGEN
SPECIES (ROS). Tissue responses to IR seem to be
directed towards limiting damage, inducing repair and
restoring tissue homeostasis. However, as with most
tissue processes, this response can be disrupted by
high doses of radiation, pre-existing conditions such
as previous exposure, and the genetic features of the
individual (Fig. 1).

. . .

+++++++++++++++++++
On Oct. 5, 1947, in the first televised White House address, President Truman asked Americans to refrain from eating meat on Tuesdays and poultry on Thursdays to help stockpile grain for starving people in Europe. 

-- John
John Jacobus, MS
Certified Health Physicist
e-mail:  crispy_bird at yahoo.com


		
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