One of the central themes
modern molecular oncology
has been the repeated observation that the development and progression of cancer
involves the inappropriate activity of normal cellular mechanisms involved in
basic processes essential to multicellular organisms, such as embryogenesis,
senescent cell replacement, growth, and wound-healing. One of the most
fundamental challenges to multicellular life is the delivery of sufficient
oxygen and metabolic substrate to all cells and the rapid elimination of acid
formed during cellular respiration. The molecular mechanisms involved in
regulating oxygen and glucose delivery and local blood flow have now been
partially elucidated; it is not surprising that these processes may also be
fundamental in tumor biology and the progression of cancer. Because these
processes evolved for the regulation of oxygen delivery, it is logical to wonder
whether anemia, by physiologically activating these pathways, contributes to the
progression of cancer.
In addition to these potential effects on cancer biology,
there is evidence that anemia may have deleterious effects on the efficacy of
cancer treatments, including radiotherapy, chemotherapy, and modern
"targeted" therapies, and on the well-being of the patient. Taken in
aggregate, these observations indicate that it is time to seriously consider the
effects of anemia on the survival of cancer patients. This article reviews the
data available regarding the impact of anemia on the survival of cancer
Prior to 1997, it was assumed mild and moderate degrees of
anemia (hemoglobin levels ≤
8 gm/dL) were insensate to cancer patients and therefore clinically unimportant
in their management. This assumption proved to be false, and it has now been
demonstrated, in both open-label[1-3] and randomized, controlled trials,[4-7]
that the quality of life of cancer patients is improved when these levels of
anemia are treated with erythropoietic agents, such as epoetin alfa (Epogen,
Procrit), epoetin beta (NeoRecormon), and darbepoetin alfa (Aranesp). These
results are consistent with earlier observations in patients with chronic renal
failure, in whom quality of life is optimized when hemoglobin levels are
maintained above 12 g/dL.
Not surprisingly, the data from studies in cancer patients
are yielding identical results with respect to optimal hemoglobin
concentrations. In a recent analysis of two large, open-label studies including
more than 4,000 patients and exploring the relationship of quality-of-life
scores to hemoglobin levels between 7 and 12 g/dL, the greatest incremental
gains in energy and quality of life for cancer patients was observed with
incremental increases in hemoglobin levels between 11 and 12 g/dL.[8a]
It is now widely accepted that the quality of life of anemic
cancer patients may improve with anemia therapy, but it is currently assumed
both that anemia does not play a significant role in the pathophysiology of
cancer, and that anemia therapy will not be associated with improvements in
tumor response or survival. However, a growing body of preclinical evidence and
some early clinical data suggest this also is an assumption regarding
cancer-associated anemia that may be disproved in the near future. It is
possible that the symptoms reported by anemic patients reflect an important
impact of this condition on their health.
Cellular Regulation of
The last 10 years have seen significant advances in the understanding
of cellular adaptive mechanisms for ensuring a steady supply of oxygen and energy;
key features of these pathways relevant to the current discussion are shown
in Figure 1. A major advance in this
field was the discovery by Semenza and colleagues of hypoxia inducible factor-1
(HIF-1), a heterodimeric transcription factor composed of an alpha and a beta
subunit.[8b] Through mechanisms that are not fully understood, but probably
involve a heme-containing molecular oxygen sensor, hypoxia results in an increase
in HIF-1-alpha gene expression within hours of hypoxic stress. Hypoxia inducible
factor-1-alpha dimerizes with constitutively expressed HIF-1-beta to form a
transcription factor that acts on the hypoxia response element to increase the
expression of a growing list of genes encoding erythropoietin: vascular endothelial
growth factor (VEGF), glucose transporters, glycolytic enzymes, transferrin,
and the transferrin receptor. HIF-1 activity is tightly regulated. Under well-oxygenated
conditions, HIF-1-alpha binds to the ubiquitin proteosomal system through a
specific recognition by the product of the von Hippel Lindau tumor suppressor
gene (pVHL), and is degraded. A significant shortening of the half-life of HIF-1-alpha
is detectable within 5 minutes of reoxygenation.
The cellular response to hypoxia involves expression of genes
involved in meeting the higher glucose demand imposed by anaerobic metabolism,
as well as increasing the delivery of oxygen and removal of acidic metabolic
byproducts through increased blood flow and hemoglobin levels.
While this is clearly an adaptive response on the part of
normal cells, there is obvious potential for interplay with the initiation and
progression of cancer. Congenital deficiency of pVHL function is associated with
an increased incidence of cancer, and somatic mutation of pVHL is an important
event in the progression of renal cell carcinoma. These observations suggest
that chronic inappropriate activation of the normal cellular responses to
hypoxic stress may be central to the initiation and progression of some cancers.
Tumor Cell Behavior
The establishment and growth of tumors require new blood
vessel formation, which occurs through a process termed angiogenesis. One of the
most important pathways for tumor angiogenesis involves the interaction of VEGF
with a family of cognate receptors that mediate a series of cellular responses
that include proliferation, migration, and survival. Levels of VEGF in tumor
cytosol preparations have been shown to correlate with a poor prognosis in early
Bevacizumab (Avastin), a humanized monoclonal antibody
directed against VEGF, is one of the new "targeted" cancer therapies
under clinical development, and has shown some promise as a single agent and
when utilized in combination with chemotherapy. These observations raise the
possibility that by increasing tumor cell hypoxia and thereby inducing
physiologic molecular alterations and increased expression of VEGF, it is
possible that anemia may unfavorably alter the behavior of cancers and/or
counteract the efficacy of targeted therapies.
Although the VEGF axis is the best characterized pathway
through which tumor cell hypoxia may increase angiogenesis and result in a more
aggressive tumor cell behavior, there are several other possible effects of
hypoxic stress. Tumor cell hypoxia results in an increased expression of
cyclooxygenase-2, connective tissue growth factor, and interleukin-8, each of
which is associated with increased angiogenesis and the induction of a more
Perhaps more importantly, recent evidence suggests that the
signaling pathways of the erb family of receptors (eg, epidermal growth
factor receptor (EGFR) and HER2/neu) include HIF-1 and increased VEGF
expression, which may mediate some of the effects of activation of these
pathways on cancer cell biology. Hence, hypoxic stress such as anemia has
the potential to interfere with the efficacy of the newer targeted anticancer
therapies, such as EGFR-blocking antibodies or direct inhibitors, anti-HER2
therapies, and antiangiogenesis treatments.
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