Research ArticleCancer

Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47

Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63ra94
DOI: 10.1126/scitranslmed.3001375

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Eat Up!

Immune cells constantly patrol the body on a search and destroy campaign against foreign invaders. Designed to detect differential molecular signals, cells of the immune system can distinguish healthy from infected tissue by the types of proteins produced: Infected cells, for example, often produce unfamiliar proteins, which then activate innate immune cells to “eat” (phagocytose) the infected ones. Cancer cells also carry aberrant cargo such as unfamiliar proteins or normal proteins at abnormal levels, yet these cells frequently escape immune attack because they express a “don’t eat me” signal, the cell surface protein CD47. Blocking this signal on a cancer cell makes them targets for phagocytosis, but surprisingly does not do the same for normal cells that express CD47. Chao et al. have now identified calreticulin as the “eat me” signal on cancer cells that leads to phagocytosis when the counterbalancing “don’t eat me” signal CD47 is blocked.

Calreticulin is a pro-phagocytic molecule that is highly expressed on the surface of several types of human cancer cells, including acute myeloid and lymphoblastic leukemias, chronic myeloid leukemia, non-Hodgkin’s lymphoma, bladder cancer, glioblastoma, and ovarian cancer. However, calreticulin is expressed only at very low levels on normal cells. Chao et al. found a correlation between calreticulin and CD47 expression levels on cancer cells and showed that blocking the interaction between calreticulin and its ligand prevented phagocytosis initiated by blocking the “don’t eat me” signal CD47. Moreover, high calreticulin expression on cancer cells was a poor prognostic indicator in human patients with neuroblastoma, bladder cancer, and non-Hodgkin’s lymphoma. Therefore, a balance between calreticulin and CD47 expression in cancer cells may be a double-edged sword: In the absence of a CD47 blocker, this equilibrium may support tumor cell survival, but when CD47 function is inhibited, the presence of calreticulin tells immune cells to “eat up!” This information provides a key insight for the therapeutic development of CD47-inhibitory agents.


  • These authors contributed equally to this work.

  • Citation: M. P. Chao, S. Jaiswal, R. Weissman-Tsukamoto, A. A. Alizadeh, A. J. Gentles, J. Volkmer, K. Weiskopf, S. B. Willingham, T. Raveh, C. Y. Park, R. Majeti, I. L. Weissman, Calreticulin is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).