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2015 Chabner Colloquium: Collaboration in Cancer Trials
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Targeting Sleeping Cancer Cells
Sridhar Ramaswamy, MD
Massachusetts General Hospital Cancer Center, Harvard Medical School
Sridhar Ramaswamy, MD
www.STO-online.org
Traditional conceptual models frame cancer as
a step-wise progression of tumor cell growth
and development. However, all cancers contain a mixture of rapidly and slowly proliferating cancer cells. This proliferative heterogeneity complicates the diagnosis and treatment of
patients with cancer because slow proliferators are hard to eradicate and can be difficult to
detect. Furthermore, slow proliferators represent an important barrier to cure, as these cells
may cause disease relapse years after apparently curative treatment. In the 15-year followup analysis of the Early Breast Cancer Trialists’
Collaborative Group (EBCTCG) trial, roughly half
of the disease recurrences and two-thirds of the
breast cancer deaths in women with estrogen
receptor (ER)-positive breast cancer occurred
after completing 5 years of adjuvant tamoxifen
therapy (Table 2).1
Clonal selection theory explains the presence and evolution of rapid proliferators
within cancer cell populations. To date, however, slow proliferators have not been well
characterized.2 How are these slowly proliferating cancer cells produced? Why do rapidly
dividing cancer cells that have been selected
for maximal proliferation continuously spawn
these slow proliferators? Are slow proliferators functionally important in cancers, or is the
proliferative heterogeneity in cell culture just
random noise?
Recent biologic insights have enabled better understanding of the process of cancer cell
dormancy. In one theoretical model, cellular
dormancy is viewed as a dynamic cell state that
confers a fitness advantage to a tumor under
stress.2 Depending on the tumor microenvironment, tumor cells can toggle through the
process of cellular dormancy by downregulating key signaling pathways that are otherwise
critical for tumor growth and survival.2 Compared with rapidly proliferating cancers, slowly
proliferating cancer cells produce low levels of
reactive oxygen species (ROS). Indeed, ROSlow cancer cells are more predominantly in the
G1/G0 stages of the cell cycle compared with
actively cycling ROS-high cells.3
Although these “G0-like” ROS-low cells
appear quiet respect to cell-cycle phase, other
biologic functions are not suppressed. In cell
culture, ROS-low cells can re-enter the cell
cycle and resume normal proliferation within
7-10 days. Therefore, ROS-low cancer cells
appear to represent a unique cancer cell population that differs from apoptotic, senescent,
autophagic, or DNA-damaged cells, cancer
stem cells (CSCs), or cells undergoing epithelial-mesenchymal transition (EMT). Moreover,
ROS-low cancer cells are ubiquitous, occurring
in low frequency (1-3%) in all human and mouse
cancer cell lines irrespective of specific oncogenomic profiles.
One of the most recent advances in understanding asymmetric cell division involved the
detailed characterization of the β1-integrin/
FAK/mTORC2/AKT1/TTC3-associated signaling pathway.4 The AKT signaling pathway plays
a key role in the production of G0-like cancer
cells. During replication, the asymmetric inhibition of AKT signaling in one emerging daughter
cell leads to nuclear localization, AKT protein
suppression, and proliferative arrest. The inhibition of AKT signaling also contributes to a distinct expression profile within G0-like daughter cells, including MKI67-low, MCM2-low,
H3K9me2-low, and HES1-high. The proliferative output of the β1-integrin/FAK/mTORC2/
AKT1/TTC3-associated signaling cascade also
involves a proteasome-dependent degradation process mediated by the E3 ubiquitin ligase
TTC3. These findings highlight potential opportunities for future therapies to target multiple
proliferative mechanisms.
The in vivo behavior of G0-like cells is
not well understood. In cell culture studies,
slowly proliferating AKT1-low cells appear to
grow preferentially in areas of irregularity in
the extracellular type I collagen matrix.4 One
emerging hypothesis suggests that G0-like
cells may populate wound-like, stress-resistant, inflammatory niches that increase the
overall fitness of cancer cell populations.
Slowly proliferating G0-like cells are highly
resistant to cytotoxic chemotherapy in cell culture and may be a major source of post-treatment relapse. Additional human studies are
underway to examine patterns of treatment
resistance in tumor cells harvested before and
© Society for Translational Oncology 2016
2
Targeting Sleeping Cancer Cells
Table 2. Late Relapse After Targeted Treatment in ER-Positive Breast Cancer1
5 Years of Adjuvant Tamoxifen
Control
5 years
85.2%
73.7%
15 years
68.2%
54.9%
5 years
91.4%
87.8%
15 years
73.0%
64.0%
Freedom from breast cancer recurrence
Freedom from breast cancer death
ER = estrogen receptor.
after cytotoxic chemotherapy (breast cancer) and hormone
therapy (prostate cancer).
Summary
Just as limitless replication potential is a hallmark of cancer,
the ability of cancer cells to enter a state of quiescence appears
to be vital for evolving malignancies as well. Proliferative heterogeneity within cancer cell populations is produced, in part,
through a targetable signaling mechanism. This emerging
model explains the phenomena of cancer cell dormancy, broad
resistance to cancer therapies, and disease relapse after treatment across cancer types. Moreover, these new insights to
tumor biology have potential implications for targeting cancer
progression, dormancy, and therapeutic resistance.
Financial Disclosures
Dr. Ramaswamy discloses no financial relationships relevant to
the content of this presentation.
Acknowledgements
This summary was created from the proceedings of the 2015
Chabner Colloquium: Collaboration in Clinical Trials, which was
held on Monday, October 26, 2015, in Boston, MA. The Society for Translational Oncology received educational grants in
support of this activity from AbbVie Inc., Chugai Academy for
Advanced Oncology (CHAAO), Epizyme, Inc., Incyte Corporation, Lilly USA, LLC, Merrimack Pharmaceuticals, Inc., Novartis
Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., and Pfizer Inc.
References
1. Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG). Effects of chemotherapy and
hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Yeh AC, Ramaswamy S. Mechanisms of can-
cer cell dormancy-another hallmark of cancer?
Cancer Res. 2015. [Epub ahead of print].
3. Dey-Guha I, Wolfer A, Yeh AC, G Albeck J, et
al. Asymmetric cancer cell division regulated by
AKT. Proc Natl Acad Sci U S A. 2011;108(31):1284512850.
© Society for Translational Oncology 2016
4. Dey-Guha I, Alves CP, Yeh AC, et al. A mechanism for asymmetric cell division resulting in
proliferative asynchronicity. Mol Cancer Res.
2015;13(2):223-230.
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