Biomedical Engineering Reference
In-Depth Information
implicated in mediating this inflammatory process in response to the
H. pylori
peptidoglycan [52].
Type 2 diabetes is characterized by insulin resistance, impaired insulin secretion,
and elevated hepatic glucose production. In addition, a strong relationship between
obesity and type 2 diabetes has been established [53,54]. Based on the fact that
obese individuals have elevated serum levels of inflammatory cytokines such as TNF
and IL-1
, it has been suggested that diabetes associated with obesity is an inflam-
matory disease [53]. In fact, mouse models linking obesity-induced type 2 diabetes
and inflammation have been established [54].
β
8.1.4 C
ANCER
M
ECHANISMS
Cancer is an extremely complex disease based on multiple etiologies, cell targets,
and developmental stages. Furthermore, most advanced cancer cells exhibit genomic
instability, leading to further complexity in the nature of the disease. However, as
described below, cancer cells exhibit common features with defects in regulatory
pathways that govern normal proliferation and homeostasis. Many of these alter-
ations are intrinsic to the cancer cells themselves, and others are manifested from
signals that emanate from the surrounding tumor microenvironment.
Hanahan and Weinberg [55] have proposed six alterations that are shared by
advanced cancer cells and that drive malignant growth: (1) self-sufficiency in
growth generating signals; (2) profound resistance to growth inhibitory signals;
(3) strong resistance to apoptosis; (4) extended replication potential; (5) the poten-
tial to induce angiogenesis; and (6) the ability to invade local tissue and to metas-
tasize to distant sites.
Self-sufficiency in growth can be provided by dysregulated expression of growth
factors or growth factor receptors leading to uncontrolled cell division. For example,
many cancers exhibit upregulation of expression of members of the epidermal growth
factor receptor (e.g., EGF receptor or Her2/ErbB2). Furthermore, cancer cells (e.g.,
glioblastoma and sarcomas) produce growth factors such as PDGF and TGF
(reviewed
in [55]). Mutations in proteins that can drive proliferation are also relatively common
in cancers. For example, mutations in Ras alleles drive proliferation through chronic
stimulation of signal transduction pathways [56]. Paracrine mechanisms involving nor-
mal bystanders or recruited inflammatory cells can also promote growth. Resistance to
growth-inhibitory signals can be achieved through mutations in tumor suppressor genes
such as p53, Rb, ARF, and antigen presenting cell (APC), or in receptors such as that
for TGF
α
. Additionally, upregulation of expression of cyclin D1 or c-myc, or activating
mutations in transcription factors such as
β
β
-catenin, can promote cell proliferation or
cell growth (see [
55
]).
A key process in the ability of tumor cells to expand locally and to metastasize
is the ability of the cell to resist apoptosis [57]. Resistance to apoptosis can involve
the activation of expression of antiapoptotic factors, such as Bcl-2 or Bcl-x
L
, or the
loss of expression or mutation of proapoptotic factors, such as p53. Alternatively,
mutations in tumor suppressors such as PTEN can lead to the activation of intrac-
ellular signaling pathways (in this case, the PI3 kinase/Akt pathway) that suppress
apoptosis [57]. An additional mechanism of suppression of apoptosis is the induc-
