br MMP and MMP are important determinants
MMP-2 and MMP-9 are important determinants of angiogenesis, invasion and cancer metastasis in breast cancer and regulate the de-gradation and remodeling of basement membranes and the ECM [57–59]. It is noteworthy that the mouse serum ELISA analysis
Fig. 7. Hypothetical model illustrating the multiple actions of L80 on tumor growth, angiogenesis and metastasis in triple-negative breast cancer cells. HSP90 directly binds to STAT3, inhibiting STAT3 phosphorylation, dimerization and nuclear translocation, thereby affecting tumor cell survival, proliferation and cancer pro-gression. We propose that (i) L80 inhibits TNBC cell proliferation by suppressing several signaling pathways including AKT, MEK/ERK, and JAK2/STAT3, (ii) L80-induced suppression of BCSC-like traits characterized by reduction of CD44, CD49f, ALDH1 activity and mammosphere-forming ability, (iii) L80 impedes tumor growth, angiogenesis and subsequently suppresses lung and liver metastatic growth, (iv) These phenomena are associated with dysregulation of STAT3 activation, coinciding with downregulation of the downstream factors 950455-15-9 D1, survivin, vimentin, and MMP-2/-9.
indicated that MMP-2 and MMP-9 levels in circulating blood were markedly elevated in allografts during metastatic progression and were significantly hampered in the presence of L80 treatment. Accumulating evidence has shown that extracellular HSP90 directly interacts with MMP-2 and MMP-9 to foster their proteolytic activity outside tumor cells, thereby promoting tumor invasiveness and angiogenesis. These responses can be attenuated by HSP90 inhibition or a HSP90 mono-clonal antibody [60–62]. It is conceivable that L80 at least in part in-hibits extracellular HSP90 leading to a reduction in MMP levels, which likely contributes to the impairment of tumor angiogenesis and meta-static spread. In summary, we have demonstrated that the C-terminal HSP90 in-hibitor L80 inhibits TNBC cell proliferation via the suppression of several signaling pathways including AKT, MEK/ERK and JAK2/STAT3 as well as BCSC-like traits such as CD44, CD49f and ALDH1 activity. L80 administration impaired tumor growth, angiogenesis, and distant metastasis via dysregulation of STAT3 activation (Fig. 7). These find-ings suggest that L80 may offer an effective therapeutic pathway for the simultaneous targeting of both HSP90 and STAT3 for the treatment of TNBC.
Conflicts of interest
The authors declare no conflict of interest.
Conception and design: JY. Kim, J. Lee and JH. Seo.
Sung and S. Jung.
Contributed reagents, materials and analysis tools: T-M. Cho, JY.
Appendix A. Supplementary data
V. Galimberti, P. Veronesi, A. Luini, G. Pruneri, L. Bottiglieri, M.G. Mastropasqua,
 B.K. Eustace, T. Sakurai, J.K. Stewart, D. Yimlamai, C. Unger, C. Zehetmeier, B. Lain, C. Torella, S.W. Henning, G. Beste, B.T. Scroggins, L. Neckers, L.L. Ilag, D.G. Jay, Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness, Nat. Cell Biol. 6 (2004) 507–514.  D. Stellas, A. El Hamidieh, E. Patsavoudi, Monoclonal antibody 4C5 prevents ac-tivation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits, BMC Cell Biol. 11 (2010) 51.
Contents lists available at ScienceDirect
CA19-9 elevation as an indication to start salvage treatment in surveillance after pancreatic cancer resection
Jiarui Li a, Zhe Li b, Haoxuan Kan a, Zhao Sun a, Jiazhang Xing a, Yuejuan Cheng a, *, Chunmei Bai a, ** a Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100032, China
b Department of Gynecologic Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Received in revised form
Available online 1 February 2019
Background: CA19-9 is the most commonly used tumor marker in the diagnosis, prognosis and sur-veillance of pancreatic cancer. We hypothesized Exonucleases CA19-9 elevation can be taken as an indication to start salvage treatment in surveillance after resection. Methods: From January 2014 and July 2017, 80 pancreatic cancer patients who underwent R0 surgical resection and received adjuvant chemotherapy were included.
Results: Twenty-six (32.5%) patients started salvage treatment at the time of CA19-9 elevation without radiological evidence of recurrence. Fifty-four (67.5%) patients treated conventionally before recurrence was confirmed by radiological examinations. Sixty (75%) patients had CA19-9 elevation that preceded radiographic recurrence by about 3 months. In the intervention group, the median DFS (23.6 months vs. 12.1 months, P < 0.001) and OS (28.1 months vs. 20.7 months, P ¼ 0.049) were significantly longer than those in the control group.