J Cancer 2017; 8(4):537-554. doi:10.7150/jca.15989

Research Paper

Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs

Anna Karolina Kozlowska1,2*, Paytsar Topchyan1*, Kawaljit Kaur1, Han-Ching Tseng1, Antonia Teruel1, Toru Hiraga3, Anahid Jewett1✉

1. The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center, Dental Research Institute, Division of Oral Biology and Oral Medicine. UCLA School of Dentistry, Los Angeles, CA 90095, USA.
2. Department of Tumor Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
3. Department of Histology and Cell Biology Matsumoto Dental University, Gobara-Hirooka, Shiojiri, Nagano, Japan.
* These authors contributed equally to the manuscript.

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Kozlowska AK, Topchyan P, Kaur K, Tseng HC, Teruel A, Hiraga T, Jewett A. Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs. J Cancer 2017; 8(4):537-554. doi:10.7150/jca.15989. Available from http://www.jcancer.org/v08p0537.htm

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Natural Killer (NK) cells target oral, pancreatic, lung, breast, glioblastoma and melanoma stem-like/poorly differentiated tumors. Differentiation of the abovementioned tumors with supernatants from split-anergized NK cells decreases their susceptibility to NK cells, but increases their sensitivity to cisplatin (CDDP)-mediated cell death. Breast and melanoma tumor cells with CD44 knockdown display enhanced susceptibility to NK cell-mediated lysis, potentially due to decreased differentiation. We also demonstrate that sulindac, a non-steroidal anti-inflammatory drug and a chemopreventive agent, not only limits the growth of oral tumor cells, but also aids in cancer cell elimination by NK cells. Treatment of oral tumors with sulindac, but not adriamycin inversely modulates the expression and function of NFκB and JNK, resulting in a significant down-regulation of IL-6, and VEGF secretion by oral tumor cells. In addition, increased secretion of IL-6 and VEGF is blocked by sulindac during interaction of oral tumors with NK cells. Sulindac treatment prevents synergistic induction of VEGF secretion by the tumor cells after their co-culture with untreated NK cells since non-activated NK cells lack the ability to efficiently kill tumor cells. Moreover, sulindac is able to profoundly reduce VEGF secretion by tumor cells cultured with IL-2 activated NK cells, which are able to significantly lyse the tumor cells. Based on the data presented in this study, we propose the following combinatorial approach for the treatment of stem-like/ poorly differentiated tumors in cancer patients with metastatic disease. Stem-like/ poorly differentiated tumor cells may in part undergo lysis or differentiation after NK cell immunotherapy, followed by treatment of differentiated tumors with chemotherapy and chemopreventive agents to eliminate the bulk of the tumor. This dual approach should limit tumor growth and prevent metastasis.

Keywords: cancer stem-like cells, NFκB, VEGF, IL-6, NSAIDs, sulindac, NK cells