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Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy., Graphical Abstract, Highlights • Apoptotic lymphoma cells promote tumor growth, angiogenesis, and TAM accumulation • Unbiased “in situ transcriptomics” analysis shows TAMs promote pro-tumor pathways • Apoptotic tumor cells express and process matrix remodeling proteins • The oncogenic potential of apoptotic tumor cells extends beyond lymphoma, Apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. Ford et al. demonstrate apoptotic lymphoma cells can promote tumor growth, angiogenesis, TAM accumulation, and TAM activation to potentiate cancer progression. These results have important implications for apoptosis-inducing anti-cancer therapies.

CONCLUSIONS (1) So small a per cent of the increasing incidence of lung cancer is resectable that efforts must be made to improve the treatment of inoperable lesions. (2) Improved equipment and technics of radio-therapy may increase palliation and survival times. (3) Internal irradiation with radio-active isotopes is a modality whose usefulness is to be explored.

The concept of total-body irradiation goes back many years. In 1905, Dessauer (1) described a set-up which would employ multiple x-ray tubes distributed around a room to achieve uniform irradiation of a whole body centrallyplaced. This was theoretical only; it did not become a reality for several years. In 1927, Krause (2) suggested total-body irradiation for the treatment of disseminated neoplasms, and in the same year, Werner Teschendorf (3) described the use of the procedure in leukemia. He administered a dose of 200 to 250 R with but one x-ray tube placed at some distance from the body; a unit functioning at 180 kvp at a distance of 150 em. In 1932, Heublein (4) in a preliminary report described a specially designed room at the Memorial Hospital for total-body irradiation. Twenty patients had been treated in this chamber, receiving doses from 37.5 to 225 R. Some improvement resulted in the lymphomas treated, no response was elicited in the leukemia patients, and slight improvement was noted in patient...

Teletherapy sources such as cobalt 60 and cesium 137 have been used for localizing studies in conjunction with radiation therapy for some time. In fact, one of the few references in the literature (1) points out that, under certain circumstances, radiography with these high-energy sources can provide diagnostic information beyond that provided by routine radiography. In view of the obvious advantages to using the teletherapy source for radiographic localization, it is surprising that so little has appeared concerning the procedure in the literature. This may well be due to the equally obvious limitation imposed on a radiographic system in which the energy of the radiation results in practically 100 per cent Compton interaction with the subject. Since Compton interactions are essentially independent of atomic number, the resulting differentials in absorption for the various structures in the human body are not very large and contrast, therefore, is at a minimum. In high-energy radiography, the proper filmi...

In the past few years there has been a rapidly growing interest in the problems of radiation protection in cases of exposure of large areas of the human body. In addition, much work has been done in the field of organ transplants, particularly with respect to the management of leukemia with bone-marrow transplants. It is of interest to note that more success has attended the studies on experimental animals than on man. It is postulated that one of the problems in evaluating the efficacy of total-body irradiation of man has been the difficulty of obtaining a fairly uniform dose of radiation throughout the entire volume of a patient. Certainly a system which provided such a uniform energy deposition would eliminate a variable in the ultimate evaluation of total-body irradiation. It is the object of this paper to describe a physical system designed and constructed with this in view and to report the initial results of the dosimetry connected with it, as well as the problems encountered. The irradiation chamb...

The treatment of lymphoma has, over the past half century, steadily improved, and survival rates have risen. The authors believe that this is due primarily to better radiotherapy. The advent of high-energy radiation, either from high-voltage generators or isotopes, i.e., cobalt 60 and cesium 137, has made possible higher dose irradiation to demonstrable or palpable lesions. The purpose of this paper is to explore the relationship between the quantity of radiation delivered to localized areas and the recurrences in those fields. The publications in 1958 of Peters and Middlemiss (8) gave encouragement to therapists whose observations indicated inadequate control by low dosage patterns. In the early part of this century, it was customary to employ 1,000 r or less to separate areas. Some regressions did result; however, many recurrences were noted after such limited quantities of irradiation. Peters and Middlemiss, as well as Kaplan (11, 13) have lucidly described the rationale for irradiating not only the in...

Chromic radiophosphate, Cr P 32 0 4 , was injected intrathoracically in 41 patients with pleural effusion and intraabdominally in 16 with ascites. In every case there was proof that the lesion was neoplastic and its location was known. The chromic radiophosphate was in the form of a colloidal supension with mean particle-size of 4μ and a concentration of 1 mc. of P 32 per milliliter. Good results, in the sense of relief of symptoms and cessation of the effusion, were obtained in 25 of the first group and 5 of the second group of patients. Four case histories illustrate the completeness and duration of relief so obtained, and P 32 is shown to have certain advantages over Au 198

Air embolism is not an uncommon complication when diagnostic or therapeutic measures using air under pressure are employed. Air embolism also occurs when the air is not under pressure. In either instance there must be a break in the continuity of a vessel, either artery or vein, and the open vessel must contain blood under less pressure than the surrounding air. Of particular interest and concern to the obstetrician are those situations involving the female genital tract that may give rise to air embolism during or shortly following pregnancy. Forbes 1 reported the case of a woman dying suddenly at three months pregnancy apparently after a self-administered douche. Autopsy revealed the right side of the heart and the pulmonary artery to be filled with frothy blood. Deadman 2 reported four cases of fatal air embolism in women anywhere from three and one-half to seven months pregnant. In three of these