Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate.

Publisher Summary This chapter summarizes the findings and hypotheses of cancer metastasis and elucidates the complex mechanisms involved in the pathogenesis of metastasis. The development of a metastasis is dependent on the interplay of host and tumor cell properties. The process is complex, highly selective, and represents the end stage of several destructive events from which few tumor cells survive. Malignant neoplasms may consist of a variety of subpopulations of cells with differing capabilities for invasion and metastasis. Only a few tumor cells within a primary neoplasm may actually invade blood vessels, and of those, even fewer survive in the circulation. The unique characteristics of tumor cells, including modifications in cell surface properties, adhesive capacities, cell motility, and enzyme secretion, are of paramount importance in determining the eventual outcome of the metastasis. Such acquired properties of malignant cells allow for interaction with host tissues and cells, which leads to tumor cell survival and growth. Three mechanisms are invoked to explain tumor cell invasion—(1) the rapid multiplication of malignant cells leading to growth and infiltration by mechanical pressure, (2) the destruction of host tissue by the products of the tumor cell, and (3) the lack of tumor cell adhesiveness accompanied by an increase in the cell motility.

The biology of cancer invasion and metastasis.

Publisher Summary This chapter discusses the immune response to chemically induced, transplantable tumors in syngeneic mice. It deals with those tumors that are immunogenic by virtue of their possession of tumor-specific, transplantation rejection antigens. A framework of evidence has been presented in the chapter that supports the hypothesis of down-regulation of antitumor immune response. Direct evidence for the hypothesis consists of the finding that infusion of suppressor spleen cells from donors with a large tumor can prevent recipient mice from generating a concomitant immune response. Additional direct evidence is being supplied by an ongoing study that shows that complete or partial regression of the Meth A fibrosarcoma that results from appropriately timed exposure to sublethal, whole-body γ-radiation is associated with a prolonged generation of effector T cells and an absence of suppressor T cells. It is suggested that down-regulation of antitumor immunity by suppressor T cells can explain the escape of only of those tumors that are immunogenic enough to evoke the generation of enough effectors T cells to cause tumor regression in the absence of suppressor T cells. This implies that the immunity generated to some tumors is too little too late to cause regression, even in the absence of the negative regulatory influence of suppressor cells. Therefore, successful immunotherapy of some established tumors, besides depending on the employment of agents capable of eliminating suppressor T cells, will also depend on the employment of agents capable of directly augmenting the generation of effectors T cells.

Down-Regulation of the Antitumor Immune Response

The nuclear factor kappa B (NF-kappa B) transcription factor regulates cellular stress responses and the immune response to infection. NF-kappa B activation results in oscillations in nuclear NF-kappa B abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor-alpha at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-kappa B nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-kappa B-dependent gene expression, which supports the idea that oscillation frequency has a functional role.

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Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription

Traditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small-cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then reimplanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared with normal lung, primary tumors, xenografts, and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture and that was not regained when the tumors were reestablished as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development.

https://cancerres.aacrjournals.org/content/canres/69/8/3364.full.pdf

A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by Culture In vitro

The unlabeled antibody peroxidase-antiperoxidase technique was used to examine human malignant prostatic tissue (primary tumors) for the presence of prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), nonspecific cross-reacting antigen (NCA), and beta-chorionic gonadotrophin (HCG). The results were compared to those obtained with normal and hyperplastic prostate tissue (BPH). All specimens of neoplastic, hyperplastic, and normal prostate tissue showed immunostaining reactions for PSA. Immunostaining for PSA was relatively uniform among samples of normal and BPH tissue, but variations with respect to intensity of PSA immunostaining were noted among prostate tumors as well as between the neoplastic cells of individual tumors. Some areas of normal or hyperplastic prostatic epithelium within tumors showed stronger staining reactions for PSA than the tumor cells themselves. Using an antiserum which was able to detect both NCA and CEA, it was found that 16 of 38 tumors (42%) had positive immunostaining reactions. Of these, 15 were subsequently shown to contain only NCA immunoreactivity, and 1 tumor had both NCA and CEA immunoreactivity. NCA, but not CEA, immunoreactivity was identified in hyperplastic prostate tissue within tumor specimens and in BPH specimens. Neither antigen was detected in normal prostatic epithelium. Three of 38 tumors (8%) were found to contain neoplastic cells with HCG immunoreactivity. HCG immunoreactivity was not identified in BPH or normal prostatic tissue. Therefore, HCG and CEA immunoreactivity appear to be tumor-associated antigens in prostate cancer which are expressed with a low incidence. The results of the study identified prostate tumors with different patterns of immunocytochemical markers: 22 of 38 tumors (58%) contained only PSA immunoreactivity; 13 of 38 tumors (34%) contained PSA and NCA immunoreactivity; 2 of 38 tumors (5%) were positive for PSA, NCA, and HCG immunoreactivity; and 1 of 38 tumors (3%) contained PSA, NCA, HCG, and CEA immunoreactivity. Apart from PSA, which was present in all tumors, the markers studied here appeared to be more frequently expressed in well-differentiated tumors than in less-differentiated tumors. Our results suggest the possibility of subclassifying prostate tumors by means of immunocytochemistry.

https://cancerres.aacrjournals.org/content/canres/44/1/285.full.pdf

Immunocytochemical evaluation of human prostatic carcinomas for carcinoembryonic antigen, nonspecific cross-reacting antigen, beta-chorionic gonadotrophin, and prostate-specific antigen.

A rabbit antiserum to ovine prolactin was used with the peroxidase-antiperoxidase method to search for immunoreactive prolactin in normal and pathological human breast and prostate. We first substantiated that the heterologous antiserum could recognize human prolactin. When sections of human anterior pituitary were exposed to the anti-prolactin serum, groups of angular-shaped cells were selectively stained. The immunostaining of pituitary cells appeared specific for prolactin since both ovine and human prolactin abolished immunostaining when they were added to the anti-prolactin serum. In contrast, human growth hormone and human chorionic gonadotropin did not eliminate immunostaining. Using this anti-prolactin serum that was capable of selective recognition of prolactin-containing cells in human tissue, we stained sections of normal breast (five cases) and normal prostate (three cases). Numerous epithelial cells in these tissues were immunostained by the antiserum. The immunostaining was abolished by deletion of the prolactin antiserum and also by use of prolaction antiserum absorbed previously with human prolactin rather than the heterologous antiserum alone. Immunostaining was not eliminated by absorption of antiserum with human growth hormone or human chorionic gonadotropin. These results suggested that the immunostaining of normal breast and prostate was related to the presence of immunoreactive prolactin in epithelial cells of these organs. In prostate, immunostaining was confined to the secretory cell population; the basal cells were not stained with anti-prolactin serum. In breast, immunostaining did not appear to be confined to secretory cells but seemed to occur throughout the breast parenchyma. The immunostaining of normal breast epithelium was markedly heterogeneous with cells lacking immunoreactivity intermixed with cells having positive reactivity. This was less pronounced in normal prostate epithelium where most secretory epithelial cells were immunostained. However, marked variation in staining intensity between acini was commonly observed in normal prostate. Sixty-four % (14 of 22) of the primary prostate adenocarcinomas which were examined showed strong staining reactions with anti-prolactin serum. Two of three metastatic tumors of prostate origin had similar strong staining reactions. Most primary tumors of the prostate with strong staining reactions were poorly differentiated infiltrating adenocarcinomas (11 of 14; 79%). By contrast, 25% (three of 12) of the well-differentiated prostate adenocarcinomas and 11% (one of nine) of the benign prostate hyperplasias which were tested showed strong staining reactions when treated with anti-prolactin serum. Seven of 12 (58%) infiltrating duct carcinomas of the breast were strongly stained with anti-prolactin serum, but most breast fibroadenomas were not stained (six of eight; 75%). None of seven adenocarcinomas of the colon tested as controls were stained by anti-prolactin serum. As was the case with normal breast and prostate, absorption of anti-prolactin serum with human prolactin but not human growth hormone or human chorionic gonadotropin abolished the immunostaining of malignant breast and prostate. These results suggested that the immunostaining of breast and prostate carcinomas was related to immunoreactive prolactin. The results reported here emphasize the value of the peroxidase-antiperoxidase method in the study of hormone target organ interactions as well as in retrospective studies of pathological materials.

https://cancerres.aacrjournals.org/content/canres/42/6/2317.full.pdf

Immunoreactive Prolactin in Epithelial Cells of Normal and Cancerous Human Breast and Prostate Detected by the Unlabeled Antibody Peroxidase-Antiperoxidase Method

The quantitative relationship between bacillus Calmette-Guerin (BCG) and tumor cells which are optimal for suppressing the growth of tumor cells in BCG-tumor cell mixtures are detrimental to the development of a sustained, systemic tumor rejection immunity in the LSTRA murine leukemia.

https://science.sciencemag.org/content/sci/191/4224/299.full.pdf

BCG inhibition of murine leudemia: local suppression and systemic tumor immunity require different doses.

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Immunotherapy of Cancer in Animals: Models or Muddles?

Human esophageal neoplasms were studied in comparison to normal, uninvolved, and preneoplastic human esophageal epithelium for the presence of human chorionic gonadotropin (HCG), human placental lactogen (HPL), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and nonspecific cross-reacting antigen (NCA) using the unlabeled antibody peroxidase-antiperoxidase technique. HCG immunoreactivity was identified in 10 of 33 squamous cell carcinomas (33%), in 1 of 6 adenocarcinomas (17%), and 1 of 6 preneoplastic esophageal lesions (17%); while 9 of 33 squamous cell carcinomas (33%) and 1 of 6 adenocarcinomas (17%) contained immunoreactive AFP. Immunoreactive HPL was detected in 6 of 33 squamous cell carcinomas (20%), but in none of the adenocarcinomas. Neither AFP nor HPL immunoreactivity was identified in the 6 hyperplastic lesions which were studied. When stained with an antiserum that was able to detect both CEA and NCA, 27 of 33 squamous cell tumors (82%) and 6 of 6 adenocarcinomas (100%) showed positive immunostaining reactions. Of these, 8 squamous cell carcinomas and 1 adenocarcinoma were subsequently shown to contain only NCA immunoreactivity, while 19 squamous cell carcinomas and 5 adenocarcinomas contained both NCA and CEA immunoreactivity. NCA immunoreactivity alone was identified in 3 of 6 preneoplastic lesions and NCA and CEA immunoreactivity in 1 of 6 preneoplastic lesions. None of the markers was detected in 8 specimens of normal esophageal epithelium which were studied as controls, nor in 6 specimens of uninvolved esophageal epithelium obtained from patients with esophageal cancer. Most tumors expressed 2 or 3 markers, and some tumors were identified which expressed up to 4 of the 5 markers investigated. Only 3 tumors failed to express any of the markers studied. No association was found between the degree of tumor differentiation and presence or absence of HCG immunoreactivity. However, HPL immunoreactivity was more common in poorly differentiated squamous cell carcinomas. In contrast, immunoreactive AFP was more common in well-differentiated squamous cell carcinomas than in other tumor types. Similarly, both CEA and NCA were more frequently expressed in well-differentiated squamous cell carcinomas, adenosquamous carcinomas, and adenocarcinomas than in less differentiated tumors. Our results suggest that HCG, HPL, AFP, CEA, and NCA are tumor-associated antigens in esophageal cancer. Therefore, they could be of value in screening tests for esophageal neoplasms and could be useful in subclassification of esophageal neoplasms.

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Immunocytochemical evaluation of human esophageal neoplasms and preneoplastic lesions for beta-chorionic gonadotropin, placental lactogen, alpha-fetoprotein, carcinoembryonic antigen, and nonspecific cross-reacting antigen.

Dallas M. Purnell

Papers

Immunocytochemical evaluation of human prostatic carcinomas for carcinoembryonic antigen, nonspecific cross-reacting antigen, beta-chorionic gonadotrophin, and prostate-specific antigen.

Immunoreactive Prolactin in Epithelial Cells of Normal and Cancerous Human Breast and Prostate Detected by the Unlabeled Antibody Peroxidase-Antiperoxidase Method

BCG inhibition of murine leudemia: local suppression and systemic tumor immunity require different doses.

Immunotherapy of Cancer in Animals: Models or Muddles?

Immunocytochemical evaluation of human esophageal neoplasms and preneoplastic lesions for beta-chorionic gonadotropin, placental lactogen, alpha-fetoprotein, carcinoembryonic antigen, and nonspecific cross-reacting antigen.