Cancer origins (theories and research)

[Rich66]

UNIQUE STRATEGIES

A new concept for cancer therapy: out-competing the aggressor

Thomas S Deisboeck and Zhihui Wang
Complex Biosystems Modeling Laboratory, Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA

author email corresponding author email
Cancer Cell International 2008, 8:19doi:10.1186/1475-2867-8-19


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Published:	12 December 2008

Abstract

Cancer expansion depends on host organ conditions that permit growth. Since such microenvironmental nourishment is limited we argue here that an autologous, therapeutically engineered and faster metabolizing cell strain could potentially out-compete native cancer cell populations for available resources which in turn should contain further cancer growth. This hypothesis aims on turning cancer progression, and its microenvironmental dependency, into a therapeutic opportunity. To illustrate our concept, we developed a three-dimensional computational model that allowed us to investigate the growth dynamics of native tumor cells mixed with genetically engineered cells that exhibit a higher proliferation rate. The simulation results confirm in silico efficacy of such therapeutic cells to combating cancer cells on site in that they can indeed control tumor growth once their proliferation rate exceeds a certain level. While intriguing from a theoretical perspective, this bold, innovative ecology-driven concept bears some significant challenges that warrant critical discussion in the community for further refinement.


Background and hypothesis

Amongst the distinct hallmarks of cancer are uncontrolled growth and extensive cellular heterogeneity [1]. The 'ecology' concept here is based on the analogy that the host organ serves as 'bio-habitat' for a rapidly expanding heterogeneous tumor cell population, and that the organ's distinct microenvironmental conditions on site only support a certain tumor growth rate and overall tumor mass – prior to the onset of metastasis [2]. If so, one wonders if a tumor could be 'out-competed' for habitat dominance by an autologous cell population that has been engineered to outgrow the tumor cell populations, yet – other than the native cancer cells – can be therapeutically controlled. One can imagine a primary, autografted tumor cell line established from the patient's own tumor (biopsied at the time of operation) that has been genetically engineered to carry an on-off switch that can trigger programmed cell death, or apoptosis, 'on demand'. The corner stone of this innovative concept is to therapeutically skip any number of tumor progression steps by deliberately inserting an autologous cell population that securely outperforms even the most aggressive native cancer cell clone (see Figure 1).




Future Oncol. 2010 Aug;6(8):1313-23.
Modern approach to metabolic rehabilitation of cancer patients: biguanides (phenformin and metformin) and beyond.

Berstein LM.
N.N.Petrov Research Institute of Oncology, Pesochny-2, Leningradskaja 68, St Petersburg 197758, Russia. levmb@endocrin.spb.ru.


TEXT

Abstract

Comparing the experience accumulated for more than 40 years in the Laboratory of Endocrinology of Petrov Institute of Oncology (St Petersburg, Russia) with similar approaches practiced elsewhere, evidence supports the reasonability of metabolic rehabilitation of patients suffering from breast cancer or other hormone-dependent malignancies. The primary objective of such approaches is to improve treatment results by ameliorating hormonal-metabolic disturbances, including excess body fat, glucose intolerance, insulin resistance and manifestations of endocrine-genotoxic switchings, and modify tissue and cellular targets or mechanisms related or nondirectly related to the aforementioned disturbances. The relevant measures may be categorized as pharmacological (antidiabetic biguanides exemplified with metformin being most popular but not exclusive) and nonpharmacological (rational nutrition, moderate physical activity and so forth) and used separately or in different combinations.

PMID: 20799876 [PubMed - in process]




Common cell pathway could lead to new treatments for autoimmune diseases and cancer
Published on July 8, 2011


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The study, published in the July 2011 issue of the journal Blood, details for the first time how the JAK-STAT pathway is activated by the protein CK2. This is important because both the pathway and protein have been previously identified as being overactive in cancer and autoimmune diseases, said the study's senior author Etty (Tika) Benveniste, Ph.D., professor and chair of the UAB Department of Cell Biology and associate director for basic science in the UAB Comprehensive Cancer Center.
"There should be a time-limited response from both of these that should be of benefit to the host, but something happens in cancer and autoimmune diseases and neither is turned off, helping diseased cells grow," Benveniste said. "In discovering that the CK2 protein activates the JAK-STAT pathway, we can now look for ways to shut down both, which is important in cancer treatment, because if you shut down only one of these, cells can still grow. These findings will help enable the development of drugs to target blocking both the pathway and the protein, of which the ultimate goal is causing cell death in tumors."

"Through this study, we provided clear evidence that activation of the JAK-STAT signaling pathway is dependent on the presence and/or activity of CK2 in tumor cells," Benveniste said. "There are a number of pharmaceutical companies that are generating inhibitors for both of these and some are in clinical trials now. Because of our observations, companies that produce these inhibitors can now test drugs that inhibit both on patients. Some of that is starting to happen now in people with myleoproliferative disorders, and future studies are planned on glioblastoma multiforme, the deadliest brain tumor, and breast cancer."

The research team, Benveniste said, wanted to know if the CK2 protein was involved in making the JAK-STAT pathway overactive because previous studies in their laboratory identified the tumor suppressor PML as a regulator of the JAK-STAT pathway, and PML is a building block of CK2.

Blood. 2011 Jul 7;118(1):156-66. Epub 2011 Apr 28.
A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway.

Zheng Y, Qin H, Frank SJ, Deng L, Litchfield DW, Tefferi A, Pardanani A, Lin FT, Li J, Sha B, Benveniste EN.

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Source

Departments of Cell Biology and.

Abstract

JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.

PMID:

21527517

[PubMed - in process]