Biomedical Engineering Reference
In-Depth Information
tumors that developed preferentially in regional lymph nodes, bone marrow,
lung, and liver (Paget, 1889). In the ''soil and seed'' metaphor, the ''soil'' refers to
the secondary site of tumor development, and perhaps the chemical signals
produced in the microenvironment at the potential site of metastasis (Langley
and Fidler, 2007; Strieter, 2001). The ''seed'' is the ostensible stem cell or tumor-
initiating cell from the primary tumor (Chung et al., 2005). Genetic variations
that affect signaling molecules in the metastatic microenvironment can impact
the ''soil'' (Crawford and Hunter, 2006; Eccles and Welch, 2007). Overexpres-
sion of cellular migration factors could encourage a faster movement or more
rapid growth of tumor cells and could challenge the capacity of immunosur-
veillance to keep a tumor in check. Upregulation of cell surface receptors on
tumor cells could provide a propitious key to unlock a fertile new ''soil'' for
them. Mutations that affect the autocrine and paracrine signaling, in for exam-
ple chemokine receptors and their effector molecules, could play an important
role on tumor growth exacerbation or inhibition. Relief of immune inhibition
is known to play an important role in immunosurveillance and could be
responsible for a significant amount of tumor escape. Variations that augment
inhibitory factors could have a protective effect by decreasing the rate of
tumorigenesis.
In a variation of this idea, called the ''homing'' hypothesis, a secondary signal
secreted by cells at the future metastatic sites ''calls'' the tumor cells and permits
them to proliferate there (Hewitt et al., 2000; Stetler-Stevenson, 2001). In this
hypothesis, the ''seed'' produces cell surface receptors able to recognize the site
demarcated by the ''soil''. Although the mechanisms of tissue specificity remain
obscure, researchers have focused on small messenger molecules as attractants
and larger cell surface receptors guiding the tumor-initiating cells or ''seeds''.
Muller (Muller et al., 2001) and Murphy (Murphy, 2001) have each focused on
chemokines and chemokine receptors as viable candidates for ''soil and seed''
signaling. Murphy (Murphy, 2001) specifically proposes a ''spatial and tem-
poral code'' made up of specific combinations of such molecules, and others
being responsible for neovascularization, metastasis, and immunosurveillance
avoidance.
Chemokines and their receptors have been implicated in three distinct stages
of neoplasia: transformation, tumor development, and metastasis. Expression
of specific receptors on KSHV-infected B-lymphocytes and the expression of
specific receptors in HIV patients, such as CCR5 or CXCR4, are sufficient to
dictate the future course of their respective diseases. Other cancers may involve
specific chemokine receptor expression (Strieter, 2001).
4.2 Metastasis
Metastasis is the most troublesome property of tumor cells (Barnhart and
Simon, 2007). The majority of cancer fatalities are due to the effect of the spread
