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Journal of Cancer Research and Practice 4 (2017) 123e126
Contents lists available at ScienceDirect
Journal of Cancer Research and Practice
journal homepage: http://www.journals.elsevier.com/journal-of-cancerresearch-and-practice
Review Article
The novel roles of stromal fibroblasts in metronomic chemotherapy:
Focusing on cancer stemness and immunity
Wen-Ying Liao a, Tze-Sian Chan b, Kelvin K. Tsai a, b, c, *
a
Laboratory for Tumor Aggressiveness and Stemness, National Institute of Cancer Research, National Health Research Institutes, Tainan City, Taiwan
Laboratory of Advanced Molecular Therapeutics, Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical
University, Taipei, Taiwan
c
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2017
Received in revised form
26 July 2017
Accepted 4 August 2017
Available online 8 August 2017
Metronomic chemotherapy involves the administration of cytotoxic chemotherapy at reduced doses
administered at regular and frequent intervals. Low-dose metronomic (LDM) chemotherapy represents
an alternative to standard maximum tolerated dose (MTD) chemotherapy as it is less toxic and offers
additional beneficial biological effects; such effects include inhibition of tumor neovascularization and
reduced recruitment of immune-suppressive cells. In desmoplastic cancers such as breast and pancreatic
cancers, carcinoma-associated fibroblasts (CAFs) in the tumor stroma constitute an important cellular
target of systemic chemotherapy, and the treatment-modulated CAFs may deleteriously influence
treatment efficacy. Herein, we reviewed the novel roles of CAFs in metronomic chemotherapy in desmoplastic cancers. We discuss the differential effects of MTD- and LDM-chemotherapy on the heterotypic
interactions among CAFs and cells in the other cancer compartments, emphasizing the roles of cancer
stem cells and myeloid-derived suppressor cells. The novel mechanistic roles of CAFs in cancer therapy
provide an additional rationale for the clinical development of LDM chemotherapy.
© 2017 Taiwan Oncology Society. Publishing services by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Carcinoma-associated fibroblasts
Metronomic chemotherapy
Cancer stemness
Myeloid-derived suppressor cells
1. Introduction
1.1. The importance of cancer-associated fibroblasts (CAFs) in tumor
microenvironment (TME)
In 1889, Stephan Paget first broached the “seed and soil” concept
to explain the importance of the TME for cancer metastasis.1 The
“soil” of tumor is composed of fibroblasts, immune cells, surrounding blood vessels, signaling molecules, and extracellular
matrix (ECM) which nourishes cancer cells. The TME is a dynamic
milieu,2 and a profound crosstalk exists between stromal cells and
immune cells. For instance, it is widely accepted that CAFs in the
TME of desmoplastic cancers secrete amounts of growth factors,
ECM components and matrix metalloproteinases (MMPs) for supporting cancer survival or proliferation. When CAFs become activated, they secrete many mesenchymal-specific proteins such as
* Corresponding author. Graduate Institute of Clinical Medicine, Taipei Medical
University, 250 Wuxing St., Xinyi Dist., Taipei City 11031, Taiwan.
E-mail address: [email protected] (K.K. Tsai).
Peer review under responsibility of Taiwan Oncology Society.
fibroblast-specific protein (FSP-1), fibroblast-activating protein
(FAP), vimentin, a-smooth muscle actin (a-SMA), cytokines, chemokines (e.g., CXCL18, CXCL12) and growth factors (e.g., VEGF,
TGFb, EGF, PDGF).3,4 Some of the CAF-derived factors play important roles in tumorigenesis and cancer metastasis. For example, the
CXCL12 (SDF-1)-CXCR4 signaling axis has been involved in bone
and breast metastasis.5,6 On the other side, chemokines such as CCchemokine ligand 2 (CCL2) and CCL5 derived from CAFs may alter
the composition of macrophage in the TME and immune cells
recruitment into tumor, including regulatory T cells (Treg) and
myeloid-derived suppressor cells (MDSCs).7 In terms of CAFocentric concept, CAFs play essential roles in the crosstalk between
various components in TME.8
1.2. Chemotherapy-activated CAFs support cancer progression
Chemotherapy remains the standard treatment for unresectable
cancer. Conventional chemotherapy is usually given in its
maximum tolerated dose (MTD) to maximize the effect to resistant
cancer cells. However, growing evidence has demonstrated that
chemotherapeutic agents target both the tumor and the associated
neighboring stroma. Treatment-altered TME can paradoxically
http://dx.doi.org/10.1016/j.jcrpr.2017.08.001
2311-3006/© 2017 Taiwan Oncology Society. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
124
W.-Y. Liao et al. / Journal of Cancer Research and Practice 4 (2017) 123e126
promote tumor progression. In a study undertaken to question the
candidate biomarkers associated with breast cancer treatment
resistance, factors such as CXCL2, MMP1, IL8, RARRES1, FGF1, and
CXCR7 were highly induced by chemotherapy in CAFs.9 WNT16B is
another important secreted protein derived from the stroma after
cytotoxic chemotherapy treatment, and it promotes cell resistance
to chemotherapy.10,11 Conventional chemotherapy can also activate
CAFs to support tumor cellular hierarchy through IL-17A, and
induce remodeling of the TME.12 From this, CAFs which have been
“educated” through the process of chemotherapy are accomplices
during aggressive tumor progression.
1.3. Metronomic chemotherapy prevents the effects of therapyactivated CAFs
Metronomic chemotherapy, which is defined as repeated
administration of anti-neoplastic drugs at low doses frequently and
without long drug-free period, renders a “cytotoxic” conventional
chemotherapy into “therapeutic” by additional mechanisms,
including inhibition of angiogenesis and stimulation of the immune
system.13e15 In our recent work, we demonstrated that MTD
chemotherapy could lead to accumulation of CAFs in the tumor
stroma and induce oncogenic functions of CAFs in pancreatic ductal
adenocarcinoma (PDAC) through the stromal-epithelial ELR-motifpositive (ELRþ)-chemokine/CXCR2 signaling axis. The paracrine
signaling resulted in tumor stemness, neovascularization, tumorassociated macrophages (TAMs) infiltration, and tumor aggressiveness.16 A relevant study using the CYTOF platform and SPADE
analysis showed that a significant enrichment of MDSC subpopulation was found in breast cancer PDX mice models with MTDcapecitabine regimen.17 On the contrary, low-dose metronomic
(LDM) chemotherapy regimen prevented therapy-induced activation of CAFs and attenuated ELRþ-chemokines production. Additionally, it reduced the recruitment of TAMs and MDSCs and
attenuated cancer aggression. Therefore, understanding how LDM
chemotherapy may enhance host immune response is an important
subject that needs to be addressed.
1.4. The impact of therapy-activated CAFs on cancer stem cells
Tumors are highly heterogeneous structures which contain a
distinct subset of cancer cells termed cancer stem cells (CSCs).
These cells are able to self-renew and generate the diverse cell
types in the tumor.18 CSCs are intrinsically resistant to therapy, and
their proportion increases following systemic treatment, facilitating tumor relapse.19 The homeostasis of CSCs is regulated by
neighboring signals provided by surrounding stromal cells of the
TME. The copious crosstalk among CSCs and cells in the TME is
mediated by soluble paracrine factors from the different types of
stromal cells.20e22 In keeping with this paradigm, inflammatory
mediators, such as interleukin (IL)-6, and IL-8, have been found to
be substantially involved in the regulation of CSCs, contributing to
cancer invasion and metastasis.23e25 When the TME becomes
injured and damaged by systemic chemotherapy, for example, CAFs
will respond and become a resistant stromal cell type that contributes greatly in therapy resistance, mediated by enhancing tumor stemness. Conventional chemotherapy may activate CAFs to
maintain colorectal CSCs which lead to tumor progression.12 Our
previous report showed that traditional cytotoxic chemotherapy
induced secretion of ELRþ-chemokines, which signal through
CXCR-2 on carcinoma cells to trigger their phenotypic conversion
into CSCs and promoted their invasive behaviors, leading to paradoxical tumor aggression following therapy. Interestingly, the effects can be tempered by changing the administration scheme to
metronomic chemotherapy.16 These studies illustrated the
importance of stroma in cancer therapy, and how its impact on
treatment resistance could be induced by promoting tumor
stemness.
1.5. The relationship between therapy-activated CAFs and tumor
immunity
Immuno-oncology is a new focus in the field of novel drug
development. Immuno-checkpoint inhibitors hold great promise as
a treatment for cancer. The most impressive effect of immune
checkpoint blockade is its success regarding prolonging patient
survival and inducing long-lasting tumor regression.26e28 A metaanalysis of 1861 patients with advanced melanoma who received
ipilimumab, an anti-CTLA-4 monoclonal antibody, followed up for
3e10 years displayed approximately 20% long-term overall survival.27 However, other types of cancer such as PDAC respond
poorly to immunotherapies, suggesting alternative mechanisms of
resistance such as tumor microenvironment-driven immune suppression. CCL2 chemokine nitration resulted in the trapping of
tumor-specific T cell in the tumor-stroma, contributing to tumor
evasion from T cell surveillance.29 CAFs also mediated immune
suppression through CXCL12/CXCR4 axis by decreasing the number
of T cells in the tumor immune microenviroment.30,31 Consistently,
existing studies have illustrated the importance of host immune
responses as key regulators to cancer therapy.32 Thus, the way to
overcome immunotherapy resistance in the tumor and improve the
efficacy of immune-checkpoint inhibitor remains an urgent issue.
1.6. Therapy-activated CAFs and myeloid-derived suppressor cells
In an immunosuppressive tumor microenvironment, MDSCs
play important roles in helping the tumor cell escape immune
surveillance by promoting T-cell dysfunction through a variety of
mechanisms, including oxidative stress via inducible nitric oxide
synthase and nutrient depletion mediated by arginase production.33,34 MDSCs can also secrete S100A8/9 to enhance cancer cell
survival,35 and matrix metalloproteinases (MMPs) such as MMP14,
MMP13 and MMP2 to promote tumor cell invasion.36 They also
secrete IL6 to induce CSCs through STAT3 and NOTCH signaling.37
MDSCs can be phenotypically and morphologically divided into
the monocytic (Mo-MDSCs; CD11bþLy6ChiL6Glow) and the granulocytic (Gr-MDSCs; CD11bþLy6ClowL6Ghi) subsets in mice. MoMDSCs mainly express CD11b and the chemokine receptor CCR2,
and expand in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or CCL2.38,39 On one hand, a study
using a murine liver tumor model indicated that FAP-expressing
CAFs were a major source of CCL2, which enhanced the recruitment of MDSCs through FAP-STAT3-CCL2 signaling,40 on the other
hand, the trafficking of Gr-MDSCs to the tumor relies primarily on
their expression of CXCR2.41,42 In humans, LinHLADR-CD33þCD11bþMDSCs isolated from the blood of patients with
cancers are found to be immunosuppressive, and their levels increase especially in patients with high metastatic tumor burden.43
However, little is known about the crosstalk between CAFs and
MDSCs after chemotherapy treatment. It is generally understood
that MTD chemotherapy-treated CAFs can drive oncogenic activities and induce ELRþ-chemokine production. However, whether
CAFs in chemotherapy-treated desmoplastic tumors could
contribute to immune surveillance, and if so, whether this can be
avoided by tuning the way to metronomic chemotherapy remain
key questions to be addressed in the future.
2. Conclusion and future directions
To date, a number of clinical trials have supported either LDM
W.-Y. Liao et al. / Journal of Cancer Research and Practice 4 (2017) 123e126
125
Fig. 1. The schematic displays the proposed mechanisms underlying the pro-oncogenic functions of therapy-activated CAFs.
chemotherapy alone or in combination with targeted therapeutics
or anti-angiogenic drugs to be an effective approach in cancer
treatment.44,45 For instance, in patients with breast cancer, it has
been estimated that LDM chemotherapy yielded an average
response rate of 39%, with an average overall clinical benefit of 57%.
Recently, a large randomized phase III trial, the CAIRO3 trial, provided solid support for the clinical benefits of maintenance LDM
chemotherapy in metastatic colorectal cancer.46 In our recent
study, we have undertaken elegant molecular and in vivo studies to
demonstrate the role of therapy-modulated CAFs on the treatment
outcome
of
desmoplastic
cancers.
Specifically,
MTDchemotherapy-treated CAFs were proficient in promoting tumor
aggression, invasiveness and progression by bolstering cancer
stemness through the CAF-specific NF-kB/STAT1-ELRþ-chemokineCXCR2 paracrinal signaling. The same paracrine signaling process
also led to increased angiogenesis and immunosuppressive
macrophage infiltrations following MTD chemotherapy, which
further promoted tumor progression (see Fig. 1). By contrast, LDM
chemotherapy can temper the inadvertent activation of CAFs and
improve cancer treatment outcomes.
Our study also raises the possibility of the role of MDSCs in
chemotherapy-induced stromal changes and treatment outcome in
desmoplastic cancer. ELRþ-chemokine, including CXCL1, CXCL2,
CXCL5 and CXCL8, have been shown to be elevated in various types
of solid cancers, including breast cancer,35,36 pancreatic cancer,42
colorectal cancer47 or sarcomas.41 Since genetic deletion or pharmacological inhibition of CXCR2 or its ligands blunt the tumortrafficking of Gr-MDSCs and enhanced the anti-tumor efficacy of
PD1 therapy for several types of malignancies,35,41,42 we posit that
the ELRþ-chemokines secreted by MTD-chemotherapy-treated
CAFs in desmoplastic cancers would induce the trafficking of
CXCR2-positive Gr-MDSCs into the tumor stroma, contributing to
the immune-suppressive microenvironments of the tumor
following the therapy, thereby promoting tumor progression and
resistance to immune-modulatory agents. If so, the therapyinduced MDSCs recruitment and immune suppression can be prevented or at least tempered by adopting the LDM chemotherapy
regimens, which are associated with attenuated ELRþ-chemokine
production from CAFs. In this regard, we presume that LDM
chemotherapy may have a better synergistic effect with immunemodulatory agents such as immune checkpoint blockade therapy
than the traditional MTD chemotherapy in desmoplastic cancers.
Further proof-of-principle preclinical studies and clinical trials are
warranted to support this new therapeutic concept, which may
provide a novel avenue to enhance the treatment outcomes of
patients with desmoplastic cancers.
Conflict of interest
The authors declare no conflicts of interest in this study.
Acknowledgments
This work was supported in part by grants MOST 102-2628-B400-MY3, MOST 104-2314-B-400-022-MY3 and MOST 103-2314-B400-019 from Ministry of Science and Technology, Taiwan, and
NHRI CA-103-SP-01 and NHRI-014-A1-CASP01-014 from National
Health Research Institutes, Taiwan (K.K. Tsai).
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