Go or Grow !

An ominous feature of most cancers is their ability to metastasize to distant organs that is often the major cause of cancer patient’s death. It is important to fully understand this multi-step process of migration involving local invasion, intravasation, survival in the circulation, extravasation and colonization in order to effectively devise ways to control it and defeat the cancer. The kinetics of metastasis differs between different tumor types as some recurrences may happen decades after the initial diagnosis and treatment such as in breast cancers while some within a few months after initial diagnosis such as lung cancers. Although studies on how cancer cells disseminate into circulation (viz-a-viz circulating tumor cells or CTCs), manage to evade the immune system, survive latently in distant micrometastatic sites and reacquire competency are underway, we are far from a solution to control metastasis. Further, it is unclear why some tumors spread only to certain target tissues than others. For instance, prostate cancers spread largely to bone and ocular melanomas metastasize mainly to the liver. These variations could be due to differential regulation of migration and proliferation by different organ systems (1).

An interesting observation was seen recently that tumor cell populations had several distinct populations of highly proliferative and highly invasive cells that appeared to be mutually exclusive involving different molecules and pathways (2). However, it was not known how the cells shuttle between the two states and how the cell decides to follow any one of the two strategies. This phenomenon was termed as the “go or grow” or “proliferation-invasion dichotomy”. A notable finding was of Kinesin KIF11, a mitotic regulator and molecular motor protein involved in both cell growth and motility in Glioblastoma (GBM), a highly lethal primary tumor of the central nervous system (3). Although GBM is rarely known to metastasize outside of the brain, they have a very grim prognosis being highly invasive within the brain parenchyma and known to recur unscrupulously within a span of 14 months roughly 2cms next to the primary site of resection. Our initial hypothesis that cancers progressed solely by accumulation of mutations does not seem to hold good in case of GBM due to its short recurrence time (4). Highly invasive and self-renewing tumor initiating cells (TICs) with stem-cell like properties that are resistant to radiotherapy and chemotherapy are known to drive these tumors. Using a small molecule inhibitor of KIF11, Ispenesib compromised both growth and invasion of treatment resistant TICs as well as non-TICs thus prolonging survival (3). Another candidate marker contributing to this dual role is carboxipeptidase E (CPE), a neuropeptide-processing enzyme, that was found to be downregulated in gliomas under hypoxic or glucose deprived conditions; further knockdown or inhibition of CPE promoted strong migration and was linked with worse prognosis. In contrast, although overexpression of CPE decreased migration it was associated with high proliferative rate in gliomas that appeared to be dependent on oxygen and nutrition cues (5).

As more such candidates are revealed we will be better able to understand what controls cell fate decisions and we will be able to assess their prognostic implications for patient survival, especially for fast progressing and recurrent tumors like GBM.

References

1. Garay, T., Juhasz, E., Molnar, E., Eisenbauer, M., Czirok, A., Dekan, B., Laszlo, V., Hoda, M. A., Dome, B., Timar, J., Klepetko, W., Berger, W., and Hegedus, B. (2013) Cell migration or cytokinesis and proliferation?–revisiting the “go or grow” hypothesis in cancer cells in vitro, Exp Cell Res 319, 3094-3103.
2. Hecht, I., Natan, S., Zaritsky, A., Levine, H., Tsarfaty, I., and Ben-Jacob, E. (2015) The motility-proliferation-metabolism interplay during metastatic invasion, Sci Rep 5, 13538.
3. Venere, M., Horbinski, C., Crish, J. F., Jin, X., Vasanji, A., Major, J., Burrows, A. C., Chang, C., Prokop, J., Wu, Q., Sims, P. A., Canoll, P., Summers, M. K., Rosenfeld, S. S., and Rich, J. N. (2015) The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma, Sci Transl Med 7, 304ra143.
4. Hatzikirou, H., Basanta, D., Simon, M., Schaller, K., and Deutsch, A. (2012) ‘Go or grow’: the key to the emergence of invasion in tumour progression?, Math Med Biol 29, 49-65.
5. Horing, E., Harter, P. N., Seznec, J., Schittenhelm, J., Buhring, H. J., Bhattacharyya, S., von Hattingen, E., Zachskorn, C., Mittelbronn, M., and Naumann, U. (2012) The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress, Acta Neuropathol 124, 83-97.