Page 625 - Read Online

Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16 Page 13 of 24
+
tumor cells thereby facilitating killing by CD8 T cells [235] , it is plausible that additional mechanisms may be
involved. One possibility is suppression of tumor angiogenesis by the secretion of anti-angiogenic factors,
+
such as CXCL9 and CXCL10 by CD4 T cells [235] . Another putative mechanism is induction of senescence.
+
CD4 Th1 T cells also produce TNF-α, which in combination with IFN-γ induces an irreversible state of
cellular senescence keeping DTC dormant [235,236] . Ongoing projects in our lab are aimed at unraveling the
effectors steps.

BREAKING DORMANCY: IMPACT OF INFLAMMATION
Clinical and experimental observations indicate that dormant tumor cells can resume proliferation
and generate macroscopic metastases at various times after primary tumor treatment [17,85] . Escape from
dormancy could be initiated by cell autonomous events, such as oncogenic mutation or inactivation of
tumor suppressor genes. Alternatively, alterations in the host micro- or macro-environment may promote
escape from dormancy. Metastatic growth following surgical removal of the primary tumor itself is often
observed in clinical settings with predictable patterns, including in breast cancer [16,86,237-241] . Reconstructive
surgery after mastectomy for breast cancer significantly accelerates relapse rates proportionally to the
extent of surgery, when compared to primary surgery. However, no worsening in long-term survival was
reported, consistent with an effect on breaking dormancy and accelerating progression but not altering the
overall outcome [242] . Enhancement of metastatic growth induced by experimental surgery has been long
observed in animal models, suggesting that surgical wounding itself may be directly involved in breaking
dormancy [243-245] . Recently Krall et al. [246] described an experimental model that links the wound-healing
response after surgery to the outgrowth of DTC at distant sites. The link is mediated by the systemic
inflammatory response induced after surgery suppressing a tumor-specific T cell response, thereby resulting
in tumor growth. Consistent with these findings, perioperative anti-inflammatory treatment significantly
reduced tumor outgrowth. Epoxyeicosatrienoic acids, a family of pro-inflammatory molecules, stimulated
escape from dormancy in several tumor models independently of the primary tumor and was associated
with increased production of VEGF by endothelial cells [247] . Recently, it was reported that lung inflammation
[248]
promotes escape from tumor latency by inducing ZEB1 expression, a regulator of the EMT . Another
recent study reported that neutrophil extracellular traps (NET) produced by neutrophils during repeated
acute inflammation awaken dormant cancer cells in a mouse model of breast cancer [249] . The releasing of
neutrophil elastase and MMP9 from NET then remodel laminin in the extracellular matrix rendering it
accessible to a3β1 integrin. Ligated a3β1 integrin leads to the activation of FAK, ERK and MLC2 signaling
resulting in the awakening of the dormant cancer cells [249] .

[91]
Clinical and experimental evidence suggests that sustained inflammation may also promote relapses .
Correlations between inflammation at primary tumor site and risk or recurrences were reported for several
cancers including oral [250] , endometrial [251] and breast cancers [250,252] . Elevated levels of circulating C-reactive
protein and serum amyloid A, two proteins of the inflammatory response, are associated with reduced
overall survival in breast cancer, independently of body mass index, age and tumor type and stage, consistent
with inflammation being involved in breaking dormancy [253] . Interestingly, perioperative administration
of the analgesic nonsteroidal anti-inflammatory drug (NSAID) ketorolac was reported to suppress early
breast cancer relapse particularly in TNBC patients [254] and to reduce distant recurrences in patients with
increased BMI [255] . Taken together, there is compelling clinical and experimental evidence indicating that
inflammation promotes breast (and other) cancer relapses by breaking dormancy.

OUTLOOK AND PERSPECTIVES
Tumor dormancy is widely accepted as one discrete step during multistage tumor progression and bears
considerable therapeutic potential [256] . The rapid translation of this innovative concept to the patient is
limited by the paucity of therapeutic tools currently available in the clinic. Treatments directly aimed at DTC