Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNA-cisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

Molecular mechanisms of cisplatin resistance

Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Tumours may be intrinsically drug-resistant or develop resistance to chemotherapy during treatment. Acquired resistance is a particular problem, as tumours not only become resistant to the drugs originally used to treat them, but may also become cross-resistant to other drugs with different mechanisms of action. Resistance to chemotherapy is believed to cause treatment failure in over 90% of patients with metastatic cancer, and resistant micrometastic tumour cells may also reduce the effectiveness of chemotherapy in the adjuvant setting. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanisms of drug resistance that operate to reduce drug sensitivity in cancer cells. Drug resistance can occur at many levels, including increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. Advances in DNA microarray and proteomic technology, and the ongoing development of new targeted therapies have opened up new opportunities to combat drug resistance. We are now able to characterize the signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before. This will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity. The ability to predict response to chemotherapy and to modulate this response with targeted therapies will permit selection of the best treatment for individual patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1706

Molecular mechanisms of drug resistance

Numerous innate and adaptive immune effector cells and molecules participate in the recognition and destruction of cancer cells, a process that is known as cancer immunosurveillance. But cancer cells avoid such immunosurveillance through the outgrowth of poorly immunogenic tumour-cell variants (immunoselection) and through subversion of the immune system (immunosubversion). At the early stages of carcinogenesis, cell-intrinsic barriers to tumour development seem to be associated with stimulation of an active antitumour immune response, whereas overt tumour development seems to correlate with changes in the immunogenic properties of tumour cells. The permanent success of treatments for cancer might depend on using immunogenic chemotherapy to re-establish antitumour immune responses.

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Cancer despite immunosurveillance: immunoselection and immunosubversion

Acquisition of the ability to evade cellular suicide, or apoptosis, is one of the master switches that contributes to cellular transformation and, ultimately, to invasive cancer. Much has been learned about the molecular organization of apoptotic pathways and their regulators, but the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge. Survivin is an attractive candidate for cancer therapy, so what is its potential applicability in the clinic?

Validating survivin as a cancer therapeutic target.

We examined whether survivin acts as a constitutive and inducible radioresistance factor in pancreatic cancer cells. Using a quantitative TaqMan reverse transcription-polymerase chain reaction for survivin mRNA in five pancreatic cancer cell lines, we found an inverse relationship between survivin mRNA expression and radiosensitivity. PANC-1 cells, which had the highest survivin mRNA levels, were most resistant to X-irradiation; MIAPaCa-2 cells, which showed the least survivin mRNA expression, were the most sensitive to X-irradiation. Our results suggested that survivin could act as a constitutive radioresistance factor in pancreatic cancer cells. To determine whether radioresistance is enhanced by induction of survivin expression by irradiation, PANC-1 and MIAPaCa-2 cells were subjected to sublethal doses of X-irradiation followed by a lethal dose. Survivin mRNA expression was increased significantly in both PANC-1 and MIAPaCa-2 cell lines by pretreatment with a sublethal dose of X-irradiation, as was cell survival after exposure to the lethal dose. In this system, enzymatic caspase-3 activity was significantly suppressed in cells with acquired resistance. These results suggest that survivin also acts as an inducible radioresistance factor in pancreatic cancer cells. Survivin, then, appears to enhance radioresistance in pancreatic cancer cells; inhibition of survivin mRNA expression may improve the effectiveness of radiotherapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2000.tb00906.x

Survivin as a radioresistance factor in pancreatic cancer.

Livin, a recently described member of the inhibitor of apoptosis protein (IAP) family, contains a single baculovirus IAP repeat and a carboxyl-terminal RING finger (1)(2)(3). Like other proteins in the IAP family, livin binds specifically to a terminal effector cell-death protease, in this instance, caspase-9 (1)(2)(3). The consequences are substantially reduced caspase activity and reduced cell death in response to diverse apoptotic stimuli (1)(2)(3). Semiquantitative reverse transcription-PCR methods have detected human livin mRNA in fetal kidney, heart, and spleen and in adult tissues such as heart, lung, spleen, ovary, and placenta (4). In addition, livin mRNA is overexpressed by some cancer cells, including melanoma, breast cancer, cervical cancer, colon cancer, prostate cancer, leukemia, and lymphoma cells (4).

As with survivin overexpression (5)(6)(7), livin overexpression by cancer cells may lead to anti-livin antibody responses and cytotoxic T-lymphocyte responses against the cancer. In the present study, we examined livin mRNA expression in gastrointestinal cancer cell lines and the prevalence of antibody responses against livin in patients with various gastrointestinal cancers.

We cultured human pancreatic cancer cell lines (PANC-1, Capan-1, AsPC-1, MIAPaCa-2, and BxPC-3), gastric cancer cell lines (MKN-1, MKN-45, and TMK-1), colon cancer cell lines (HT-29, SW480, SW620, and LSI180), and a hepatoma cell line (HepG2) in RPMI-1640 with 100 mL/L calf serum at 37 °C in 5% CO2. Livin mRNA expression was quantified by a previously reported method (8). The sequence of the forward primer was 5′-TCAGTTCCTGCTCCGGTCA-3′, that the reverse primer was 5′-CGTCTTCCGGTTCTTCCCA-3′, and the sequence of the TaqMan probe was 5′-CCACAGTGTGCAGGAGACTCACTCCC-3′. As an internal control, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA was used and amplified with TaqMan control reagents (Perkin-Elmer Applied Biosystems). The conditions of the one-step reverse transcription-PCR have been described previously …

/pdf/detection-of-anti-livin-antibody-in-gastrointestinal-cancer-1k2x1yxc0o.pdf

Detection of anti-livin antibody in gastrointestinal cancer patients.

Using gene-transduced pancreatic cancer cells, we examined whether survivin expression is directly involved in regulation of radiosensitivity. Ordinarily radiosensitive MIAPaCa-2 cells transduced with wild-type survivin gene (MS cells) proliferated more rapidly than cells transduced with control vector. MS cells were significantly less radiosensitive than control vector-transduced cells. Radiation-induced activity of caspase-3, but not caspase-7, was significantly inhibited in MS cells. On the other hand, transduction of a dominant-negative mutant survivin gene into radioresistant PANC-1 cells augmented radiosensitivity. Further, the radiation-induced increase in caspase-3 activity was enhanced, indicating that survivin function was truly inhibited. These results indicate that survivin expression directly down-regulates radiosensitivity.

A role for survivin in radioresistance of pancreatic cancer cells.

Survivin enhances telomerase activity via up-regulation of specificity protein 1- and c-Myc-mediated human telomerase reverse transcriptase gene transcription.

Koichi Asanuma

Papers

Survivin as a radioresistance factor in pancreatic cancer.

Detection of anti-livin antibody in gastrointestinal cancer patients.

A role for survivin in radioresistance of pancreatic cancer cells.

Survivin enhances telomerase activity via up-regulation of specificity protein 1- and c-Myc-mediated human telomerase reverse transcriptase gene transcription.

Detection of autoantibodies to survivin and livin in sera from patients with breast cancer