Patient survival by Hsp70 membrane phenotype

Pfister, Karin; Radons, Jürgen; Busch, Raymonde; Tidball, James G.; Pfeifer, Michael; Freitag, Lutz; Feldmann, H.J.; Milani, Valeria; Issels, Rolf D.; Multhoff, Gabriele

doi:10.1002/cncr.22864

Cited by 93 publications

(54 citation statements)

References 46 publications

(53 reference statements)

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“…These findings might be explained by the fact that membrane Hsp70 might facilitate metastases, support adherence of tumor cells to endothelial cells and organs, or might confer resistance to an unfavorable milieu during metastasis. In line with these findings we could show that overall survival of patients with membrane Hsp70-positive squamous cell carcinomas of the lung and lower rectal carcinomas was significantly reduced compared to those patients with membrane Hsp70-negative tumors (Pfister et al, 2007). Apart from solid tumors also bone marrow samples of patients suffering from acute (AML) and chronic (CML) myeloid leukemia are frequently membrane Hsp70-positive (Gehrmann et al, 2003).…”

Section: Heat Shock Proteins and Tumorigenesissupporting

confidence: 58%

Chronic Inflammation in Cancer Development

Multhoff¹,

Molls²,

Radons³

2012

Front. Immun.

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Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression, and metastatic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions.

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Section: Heat Shock Proteins and Tumorigenesissupporting

confidence: 58%

Chronic Inflammation in Cancer Development

Multhoff¹,

Molls²,

Radons³

2012

Front. Immun.

Self Cite

409

343

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“…Recent studies confirmed that a reduction or depletion of hepatic NK cells could enhance tumor growth in the liver (19), whereas enhanced NK activity contributed to reduced liver metastases in several tumor models (20,21). Moreover, indirect evidence suggests that susceptibility of human cancer cells to NK-mediated immune attack can affect their ability to generate liver metastases (22).…”

Section: Cells Of the Hepatic Sinusoid Can Kill Tumor Cellsmentioning

confidence: 97%

The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

et al. 2013

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The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrowderived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment. Cancer Res; 73(7); 2031-43. Ó2013 AACR.

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“…This membrane form of Hsp70 is widely expressed on cultured cancer cells, including leukemic cells [23], [24], lung [12], colorectal [16], [25], and breast cancer cells [19]. Furthermore, an ongoing screening program which currently includes the analysis of primary tumors from over 1,000 patients has demonstrated that this membrane form of Hsp70 is also present on approximately 50% of all tumor entities tested, including leukemia [26], [27], melanoma [28], gastrointestinal [25] and breast tumors [29].…”

Section: Introductionmentioning

confidence: 99%

Tumor Imaging and Targeting Potential of an Hsp70-Derived 14-Mer Peptide

et al. 2014

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BackgroundWe have previously used a unique mouse monoclonal antibody cmHsp70.1 to demonstrate the selective presence of a membrane-bound form of Hsp70 (memHsp70) on a variety of leukemia cells and on single cell suspensions derived from solid tumors of different entities, but not on non-transformed cells or cells from corresponding ’healthy‘ tissue. This antibody can be used to image tumors in vivo and target them for antibody-dependent cellular cytotoxicity. Tumor-specific expression of memHsp70 therefore has the potential to be exploited for theranostic purposes. Given the advantages of peptides as imaging and targeting agents, this study assessed whether a 14-mer tumor penetrating peptide (TPP; TKDNNLLGRFELSG), the sequence of which is derived from the oligomerization domain of Hsp70 which is expressed on the cell surface of tumor cells, can also be used for targeting membrane Hsp70 positive (memHsp70+) tumor cells, in vitro.Methodology/Principal FindingsThe specificity of carboxy-fluorescein (CF-) labeled TPP (TPP) to Hsp70 was proven in an Hsp70 knockout mammary tumor cell system. TPP specifically binds to different memHsp70+ mouse and human tumor cell lines and is rapidly taken up via endosomes. Two to four-fold higher levels of CF-labeled TPP were detected in MCF7 (82% memHsp70+) and MDA-MB-231 (75% memHsp70+) cells compared to T47D cells (29% memHsp70+) that exhibit a lower Hsp70 membrane positivity. After 90 min incubation, TPP co-localized with mitochondrial membranes in memHsp70+ tumors. Although there was no evidence that any given vesicle population was specifically localized, fluorophore-labeled cmHsp70.1 antibody and TPP preferentially accumulated in the proximity of the adherent surface of cultured cells. These findings suggest a potential association between membrane Hsp70 expression and cytoskeletal elements that are involved in adherence, the establishment of intercellular synapses and/or membrane reorganization.Conclusions/SignificanceThis study demonstrates the specific binding and rapid internalization of TPP by tumor cells with a memHsp70+ phenotype. TPP might therefore have potential for targeting and imaging the large proportion of tumors (∼50%) that express memHsp70.

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Patient survival by Hsp70 membrane phenotype

Cited by 93 publications

References 46 publications

Chronic Inflammation in Cancer Development

Chronic Inflammation in Cancer Development

The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications

Tumor Imaging and Targeting Potential of an Hsp70-Derived 14-Mer Peptide

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