https://jivaresearch.org/research/curcumin/Inflammation_and_cancer-_how_hot_is_the_link.pdf

Inflammation and cancer: How hot is the link?

The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell-associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on prolonged treatment with this cytokine are augmented, reflecting an attenuation by the sTNF-Rs of spontaneous TNF activity decay. Evidence that this stabilization of TNF activity by the sTNF-Rs follows from stabilization of TNF structure within the complexes that TNF forms with the sTNF-Rs is presented here, suggesting that the sTNF-Rs can affect TNF activity not only by interfering with its binding to cells but also by stabilizing its structure and preserving its activity, thus augmenting some of its effects.

/pdf/stabilization-of-the-bioactivity-of-tumor-necrosis-factor-by-1hpdlm2emv.pdf

Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors.

Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.

T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.

Chronic inflammation has long been associated with the development of cancer, ever since Rudolf Virchow's first observation that leukocytes were present in neoplastic tissue more than 130 years ago. Recent evidences have reignited the interest of cancer researchers in the exciting concept of an association between chronic inflammation and cancer. Tumor necrosis factor alpha (TNF-alpha), initially discovered as a result of its antitumor activity, has now been shown to be one of the major mediators of inflammation. Induced by a wide range of pathogenic stimuli, TNF-alpha induces other inflammatory mediators and proteases that orchestrate inflammatory responses. TNF-alpha is also produced by tumors and can act as an endogenous tumor promoter. The role of TNF-alpha has been linked to all steps involved in tumorigenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis. How TNF-alpha acts as a masterswitch in establishing an intricate link between inflammation and cancer is the focus of this review.

TNF: a master switch for inflammation to cancer.

Tumor necrosis factor induces proliferation of neoplastic B cells from chronic lymphocytic leukemia.

Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo

We investigated the effect of recombinant tumor necrosis factor-alpha (rTNF-alpha) and recombinant lymphotoxin (rLT) in the growth modulation of purified hairy cell leukemia (HCL) cells. In response to rTNF-alpha, HCL cells from five of eight patients showed a 3 to 23-fold thymidine incorporation above their unstimulated controls. The effect was time and dose dependent with a maximum between 10 and 25 ng/ml rTNF-alpha after 120-hr incubation. rLT (1-50 ng/ml), however, could not enhance DNA synthesis in six of six cases. Cell number of rTNF-alpha stimulated cells ranged from 2-3 x 10(6)/ml from days 0-50 whereas cell number of unstimulated controls decreased from 3 x 10(6)/ml at day 0 to 0.01-0.02 x 10(6)/ml after 50 days in culture. rTNF-alpha induced proliferation could be suppressed in all HCL cell populations by 0.3 ng/ml recombinant interferon alpha (100 U/ml rIFN-alpha). TNF binding studies in two patients revealed that both TNF-sensitive HCL cells (1,990 +/- 148 receptors/cell) as well as TNF-insensitive HCL cells (1,261 +/- 101 receptors/cell) express specific receptors for TNF-alpha. These data show that rTNF-alpha and rLT have different effects on the growth of HCL cells. In addition there is a subgroup of patients who show no response to rLT or rTNF-alpha.

Tumor necrosis factor-alpha, but not lymphotoxin, stimulates growth of tumor cells in hairy cell leukemia.

Tumour necrosis factor and hairy cell leukaemia.

Recently, we described that peripheral blood mononuclear cells (MNC) from patients with hairy cell leukemia (HCL) can be induced in vitro to produce higher levels of interferon-gamma (IFN-γ) but lower levels of IFN-α than in healthy controls [7] The reduced IFN-α production has been explained by the lack of monocytes in this disease The increased production of IFN-γ suggests an increased release of cytokines by T cells This assumption has been confirmed by Ford et al [2], who described that a conditioned medium of T4-lymphocytes from patients with HCL contains a cytokine that stimulates the growth of activated, normal B cells Kehrl et al [5] demonstrated tumor necrosis factor alpha (TNF-α) to be a stimulator of activated normal B cells, and we (Digel et al 1988) have shown recently that recombinant TNF-α stimulates the growth of purified B cells from patients with B-chronic lymphocytic leukemia (B-CLL) Based on these findings, we hypothesize that TNF is produced in B-cell disorders like HCL and that TNF may stimulate the growth of hairy cells (HC)

Possible Mechanism of Interferon Action in Hairy Cell Leukemia

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