HspAdhesion · Role of cell membrane associated Hsp70 in cancer cell adhesion and metastasis

Role of cell membrane associated Hsp70 in cancer cell adhesion and metastasis

Hsp70-1A is the major stress-inducible member of the HSP70 chaperone family. The protein is being implicated in cancer diseases with the development of resistances to standard therapies, increased invasiveness and metastasis, and poor prognosis for the patient. In normal cells Hsp70-1A is expressed only in response to external stimuli such as physical exertion and heat to deal with denatured proteins and prevent toxic aggregations in the cell. A majority of human tumors produce Hsp70-1A permanently and in high amounts. In a growing number of these tumors a significant fraction is also found associated with the cell surface (mHsp70). In this project we studied the role of mHsp70 in metastasis and the mechanism of its anchorage to the cell surface on the single cell and single molecule level. We employed a biophysical perspective to a medical problem to advance our understanding of the development of cancer diseases. (Figure 1A) High levels of Hsp70-1A have been reported to promote cell motility and the transition of across membranes. These processes are highly relevant for tumor invasion and the development of metastasis. We hypothesized that the presence of mHsp70 indicates alterations in differential adhesion and compared the interaction of mHsp70 positive and mHsp70 negative tumor cells with endothelial cells that line the inner surface of blood and lymphatic vessels. We attached individual tumor cells to a micro-cantilever to bring them into contact with the lining cells and measured the interaction forces during separation (Figure 1B). Our data revealed strong interaction of mHsp70 negative cells with blood vessel lining cells and measurably lower interaction for mHsp70 positive cancer cells. Low interaction with blood vessel represents an advantage for circulating tumor cells and could contribute to the development of distant metastasis. The mechanism of cancer exclusive anchorage of mHsp70 on the cell surface is currently unknown and discussed controversially. Hsp70-1A lacks conventional cues for translocation from the inner of the cell to the surface. The membrane anchorage may thus follow a new paradigm that could possibly apply to other cancer markers. We believe that the anchoring mechanism involves specific protein-lipid interactions and hold the key for deciphering the role of mHsp70 in cancer. We conducted investigations with the atomic force microscope on model membranes which mimicked the inner and outer leaflet of the cell membrane. We observed clusters of Hsp70-1A in very specific lipid environments that may be found predominantly in certain tumors (Figure 1C). Under normal conditions these lipids are restricted to the inner leaflet of the cell membrane. Once they translate to the surface recognition procedures are triggered that result in removal of the cell by macrophages and production of autoantibodies. Hypoxia in stressed tumor cells, e.g. in response to radiation treatment may lead to the export of these lipids. However, in association with Hsp70-1A they remain undetected by the immune system leading to the survival of cancer cells despite radiation treatment. Our findings conclusively link a possible mechanisms for anchorage of mHsp70 to a potential role in the development of resistances to radiation and chemotherapy.

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