Mitochondrial dysfunction and cancer metastasis
Emily I. Chen
Published online: 15 August 2012
# Springer Science+Business Media, LLC 2012
Abstract Mitochondria have an essential role in powering
cells by generating ATP following the metabolism of pyru-
vate derived from glycolysis. They are also the major source
of generating reactive oxygen species (ROS), which have
regulatory roles in cell death and proliferation. Mutations in
mitochondrial DNA (mtDNA) and dysregulation of mito-
chondrial metabolism have been frequently described in
human tumors. Although the role of oxidative stress as the
consequence of mtDNA mutations and/or altered mitochon-
drial functions has been demonstrated in carciongenesis, a
causative role of mitochondria in tumor progression has
only been demonstrated recently. Specifically, the subject
of this mini-review focuses on the role of mitochondria in
promoting cancer metastasis. Cancer relapse and the subse-
quent spreading of cancer cells to distal sites are leading
causes of morbidity and mortality in cancer patients. Despite
its clinical importance, the underlying mechanisms of me-
tastasis remain to be elucidated. Recently, it was demon-
strated that mitochondrial oxidative stress could actively
promote tumor progression and increase the metastatic po-
tential of cancer cells. The purpose of this mini-review is to
summarize current investigations of the roles of mitochon-
dria in cancer metastasis. Future development of diagnostic
and therapeutic strategies for patients with advanced cancer
will benefit from the new knowledge of mitochondrial me-
tabolism in epithelial cancer cells and the tumor stroma.
Keywords Cancer metastasis . Mitochondria .
Mitochondrial DNA mutations . Mitochondrial Oxidative
Stress . Breast Cancer Metastasis
More than 90 % of mortality in cancer patients is attributed to
metastases, not the primary tumors that produce disseminated
tumor cells (Gupta and Massague
; Mehlen and Puisieux
). For example, the 5-year survival rate for
patients diagnosed with stage 1 breast cancer is 98
whereas the 5-year survival rate for patients diagnosed with
metastatic breast cancer is down to 16
–20 %. Although surgi-
cal resection and adjuvant therapy can cure well-confined
primary tumors, metastatic disease is largely incurable be-
cause disseminated tumor cells spread systemically and they
often acquire resistance to existing therapeutic agents.
Therefore, our ability to treat cancer effectively largely
depends on our ability to predict the formation of macrometa-
stases and to eradicate metastatic tumors at the secondary sites.
The most important feature of metastasis is that different
tumor types can formation metastases in the same or different
). The propensity for certain
tumors to seed in a particular organ was first conversed by
Stephen Paget a century ago as the of
“seed and soil” theory.
For example, the major site of prostate cancer metastasis is the
bone (Edlund et al.
). Breast and lung cancer can colonize
similar tissues, including bone, lung, liver, and brain (Hess et
; Patanaphan et al.
), but the kinetics of metastatic
progression between these two types of cancers are different.
Breast cancer metastases are often detected following years or
decades of remission (Karrison et al.
; Schmidt-Kittler et
), whereas lung cancers establish distant macrometa-
stases within months of diagnosis (Feld et al.
). Furthermore, there is often a time gap (metastatic
latency) between organ infiltration and colonization before the
detection of clinically overt metastasis. Many questions per-
taining to the organ-specific metastasis such as the origin of
disseminated tumor cells and the molecular basis of metastatic
latency are largely unknown, but recent discoveries have
E. I. Chen (
Department Of Pharmacological Sciences & Proteomics Center
School Of Medicine, Stony Brook University,
Stony Brook, NY 11794-8651, USA
J Bioenerg Biomembr (2012) 44:619
established new paradigms that will guide future research on
The role of mitochondria in cancer metastasis
Mitochondria are the primary energy producers of the cell that
regulate intracellular energy metabolism, cell death, and free
radical (ROS) production (Karbowski
; Lambert and
; Martinou and Youle
). Human mitochondria contain a small amount
of their own DNA (mtDNA) that encodes 37 genes, all of which
are essential for normal mitochondrial function. Thirteen of
these genes encode enzymes involved in oxidative phosphory-
lation, and the remaining genes encode transfer RNAs (tRNAs)
and ribosomal RNAs (Chen et al.
; Falkenberg et al.
; Tarassov et al.
). Because mtDNA is not
associated with histones and is in close proximity of ROS
production, mtDNA is directly exposed to the damaging effect
during oxidative phosphorylation. Numerous studies have
reported the association of mtDNA mutations in human tumors,
including somatic mutations (Brandon et al.
Napolitano et al.
), tumor-specific changes in the mtDNA
copy number (Desouki et al.
; Lee et al.
; Mambo et
; Mizumachi et al.
; Selvanayagam and Rajaraman
; Tseng et al.
; Yin et al.
; Yu et al.
alteration of mitochondrial gene expression (Eng et al.
Espineda et al.
; Isidoro et al.
; Weber et al.
However, the causality of mtDNA mutations in tumor progres-
sion is not well understood. By replacing the endogenous
mtDNA of a poorly metastatic mouse tumor cell line with
mtDNA of a highly metastatic mouse tumor cell line (trans-
mitochondrial cybrids), Ishikawa et al. showed that mtDNA
mutations can enhance the metastatic potential of tumor cells
by inducing complex I defects and resulting in increased ROS
production as well as up-regulation of nuclear genes essential
for cell survival and angiogenesis (Ishikawa et al.
Additional evidence implicating the role of mitochondrial
oxidative stress in cancer metastasis comes from Goh and
colleagues (Goh et al.
). They demonstrated that targeted
increase of catalase (an anti-oxidant enzyme) in mitochondria
of a breast cancer mouse model alleviated mitochondrial
oxidative stress and dramatically reduced metastatic burden
in tumor-bearing mice (Goh et al.
As opposed to increased ROS production, mtDNA muta-
tions can also enhance cancer metastasis by promoting
apoptotic resistance in cancer cells. By creating cybrids in
breast cancer cell lines, Kulawiec et al. reported that cybrids
carrying mtDNA mutations showed a higher frequency of
lung metastasis compared to cybrids carrying wild type
mtDNA without mutations (Kulawiec et al.
mtDNA mutations constitutively activate the PI3/Akt path-
way and protect cancer cells from stress-induced cell death.
More recently, a new cancer paradigm, the
” was proposed to elucidate the involvement of mito-
chondrial metabolism and cancer metastasis. In this model,
metastatic cancer cells secrete hydrogen peroxide (H
induce oxidative stress and aerobic glycolysis in the stroma
cells, which then generate L-lactate and ketone bodies to fuel
Metastatic Cancer Cells
Mutations in mtDNA
Respiratory complex I defects
α & NFκB
Reverse Warburg Effect
No Change In ROS Production
Activation of PI3K
Cell death (apoptosis)
Fig. 1 Mechanisms of
promoting cancer metastasis
through mitochondrial DNA
mutation or dysregulation of
J Bioenerg Biomembr (2012) 44:619
the oxidative mitochondrial metabolism in epithelial cancer
cells. Sotgia et al. demonstrated this two-compartment model
by analyzing the bioenergetic status of breast cancer lymph
node metastasis (Sotgia et al.
). Using a selected panel of
metabolism markers, they showed that mitochondrial mass
and activity are increased in metastatic breast cancer cells,
whereas lymph-node associated stroma showed no sign of
altered mitochondrial mass and activity. Interestingly, we
had a similar observation in metastatic breast cancer cells in
the brain. We showed that metastatic breast cancer cells capa-
ble of generating macrometastases in the brain have a dramatic
increase in oxidative metabolism enzymes compared to the
bone metastasis and primary breast tumor (Chen et al.
To assess the prognostic value of the reverse Warburg effect in
patients, Witkiewicz et al. stained human breast cancer tissue
microarrays containing tissues from triple-negative breast can-
cer patients (prone to metastasis and poor clinical outcome)
with a glycolytic marker MCT4 and found a specific correla-
tion between high stromal MCT4 expression and decreased
patient survival whereas tumor MCT4 staining had no prog-
nostic value of clinical outcome (Witkiewicz et al.
Together, these results provide new insights on how mito-
chondrial metabolism contributes to metastatic growth at the
secondary sites and demonstrate the clinical utility of meta-
bolic enzymes as biomarkers for identifying high-risk cancer
patients and as new targets for anti-cancer therapy.
In summary, the articles that comprise this minireview
volume of the Journal of Bioenergetics and Biomembranes
should provide the interested reader with an up to date view of
ongoing research in the role of mitochondria in cancer metas-
), which is attributed to greater than 90 % of
mortality in cancer patients. Clearly, dysregulation of mito-
chondrial functions in epithelial cancer cells and cancer-
associated stroma can promote the formation of clinically
overt metastasis and therefore merit continued consideration
as a therapeutic target in future research on cancer metastasis.
Also, it might be beneficial to consider developing new
antioxidant-based anti-cancer therapy to alleviate mitochon-
drial stress and prevent or reverse metastatic growth.
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