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Granulopoiesis and Thrombopoiesis in Mice Bearing Transplanted Mammary Cancer1

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Granulopoiesis and Thrombopoiesis in Mice Bearing Transplanted Mammary Cancer1 [CANCER RESEARCH 26, 149-159, January 1966| Granulopoiesis and Thrombopoiesis in Mice Bearing Transplanted Mammary Cancer1 L. DELMONTE, A. G. LIEBELT, AND R. A. LIEBELT Department of Anatomy, Baylor University College of Medicine, Houston, Texas Summary from a transplantable mouse mammary tumor (CE 1460 MA CA) that arose as a spontaneous tumor, associated with a severe Growth of a transplantable mammary cancer in CE mice (CE leukocytosis and extramedullary granulopoiesis (EMG)2, in a fe 1460 MA CA) was paralleled by hyperplasia of the granulocytic male mouse of the CE strain (22). CE 1460 MA CA has been elements of the bone marrow and peripheral leukocytosis (up to carried through more than 100 transplant generations in CE mice 350,000 leukocytes/cu mm) with a lymphoid-myeloid ratio re versal to 1:4 and a shift to the left. About 5-20% of the granulo and through more than 50 transplant generations in (BALB/C x CE) FI hybrid mice (hereafter referred to as Ft hybrids); it has cytic elements in the blood and bone marrow showed morpho logic abnormalities. Hematocrit values decreased 10-15%. shown remarkable stability as regards tumor biology and the tumor-associated hématologieresponse in both the parent strain Peripheral platelet levels manifested a slight depression in the (CE) and FI hybrid mice. face of bone marrow megakaryocytopenia and splenic mega- During a partial survey of other transplanted mouse tumors in karyocytosis. Extramedullary granulopoiesis, with the presence our laboratories, we observed a fluctuating increase in circulating of mitoses and all stages of development of the granulocyte series platelets but no leukemoid reaction to be associated with another in diffuse and discrete foci, was observed in the liver, spleen, transplantable mammary tumor (BALB/C 2301 MA CA) of lungs, lymph nodes, and adrenals of CE 1460 tumor bearers. The spontaneous origin. The specificity of this response was sug development of foci of extramedullary granulopoiesis, despite the gested by the finding that none of the other tumors studied in the absence of métastasesin the bone marrow, suggests that the survey to date evoked a comparable platelet response. former resulted from direct stimulation of both intra- and extra- Although tumor-associated hématologie changes—particu medullary hemopoietic tissue by a tumor-elaborated, granulo- larly leukemoid reactions and extramedullary hematopoiesis— cyte-specific factor, rather than from a reduction of bone marrow have been reported frequently, and reviewed extensively by space available for granulopoiesis. Dunn (5) and Ebbenhorst-Tengbergen and Mühlbock(7), it was In BALB/C mice, another transplantable mammary cancer felt that the extraction of a granulocytosis-promoting factor from (BALB/C 2301 MA CA) induced periodic fluctuation of platelets CE 1460 tumor tissue and the consequently implied possibility between base-line and elevated levels and bone marrow mega- that another humoral (thrombocytosis-promoting) factor is karyocytosis but no change in splenic megakaryoctye levels. The elaborated by the BALB/C 2301 tumor were of sufficient interest bone marrow erythroid-myeloid ratio and the peripheral leuko cytes' lymphoid-myeloid ratio remained normal. Hematocrit to warrant a study of the biology of these tumors. Hence, the present report attempts (a) to relate the leukemoid and thrombo values decreased 10-15C¿.No foci of extramedullary granulo cytic responses to tumor characteristics (e.g., growth rate, size, poiesis developed in the host tissues. and tumor viability), changes in blood morphology, and host tis The tumor specificity of the leukemoid and thrombocytic re sue histopathology, and (b) to differentiate between the host sponses was suggested by the host response to transplantation of strain-dependent and the tumor-dependent aspects of the hemo the respective tumors into (BALB/C x CE) FI hybrid mice and by poietic responses to the 2 tumors in the FI hybrid system. the regression of the specific CE 1460 tumor-associated and BALB/C 2301 tumor-associated hématologiechanges following Materials and Methods tumor excision. Hématologieand histopathologic changes were studied in 98 control and 155 tumor-bearing mice of the CE, BALB/C, and FI Introduction hybrid strains. These included: Group I (control mice), (a) 74 in A recent report from our laboratories (3) described the extrac tact young adult (6-8 weeks old) and 6 intact 3-month-old CE, tion and partial purification of a granulocytosis-promoting factor BALB/C, and FI hybrid mice, and (&) 18 intact sham-operated young adult CE, BALB/C, and FI hybrid mice; Group II (mice 1Supported in part by USPHS Grants SF3CA-17941-01/02, bearing CE 1460 MA CA), 42 young adult, 6 3-month-old, and CA-07788-01, CA-04517-03and by American Cancer Society In 13 12-month-old CE mice and 45 young adult FI hybrid hosts; stitutional Grants ACS-IN-27D-Project No. 12 and ACS-IN-27E- Group III (mice bearing BALB/C 2301 MA CA), 31 young adult Project No. 1. BALB/C and 18 young adult FI hybrid hosts. Mice were kept in Received for publication March 16, 1905; revised September 7, groups of 3 per cage, separated as to sex, and given Purina Lab 1965. Chow and drinking water ad lib. JANUARY 1966 149 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1966 American Association for Cancer Research. L. Delmonte, A. G. Liebelt, and R. A. Liebelt Each host received a s.c. implant (l cu mm) of fresh donor days in 3- and 12-month-old CE mice of both sexes. Macro- tumor tissue delivered with a trocar into the right flank on Day 1. scopically, the tumor was a homogeneous white mass that, at a Of these mice, 105 animals were killed after 2-3 weeks (Group II) diameter of approximately 15 mm, began to manifest superficial or 9-11 weeks (Group III). Another 48 hosts of Groups II and eschar formation and erosion as well as central necrosis and cystic III were subjected to excision of moderately advanced (16-22 fluid accumulation. mm in diameter) tumors, while under light ether anesthesia, and Métastasesdid not develop in the tissues of young adult CE were observed for periods up to 30 days following both successful tumor bearers, but they occasionally occurred in the form of pin and unsuccessful (i.e., local recurrence or métastases,or both) point to 3-mm foci in the lungs and livers of 3- and 12-month-old tumor excision. CE hosts during the usual 3-4 week survival period. Métastases Morning samples of caudal vein blood were obtained (a) at were also observed in the lungs of several young adult CE mice weekly intervals in intact controls, (6) prior to transplantation, which survived for exceptionally long periods of time (6-12 (c) at weekly intervals thereafter in unoperated tumor-bearing weeks) following tumor implantation. hosts, and (d) prior to operation and at 3-day intervals thereafter Tumor growth was paralleled by a marked rise in total circu in sham-operated controls and tumor-excised hosts. A single lating leukocytes (frequently to 350,000/cu mm and occasionally 13-fil blood sample, diluted 1:100 with 1.3 ml of ammonium to 750,000/cu mm) as well as by slight depression of both hemato- oxalate in an Unopette disposable blood-diluting pipette, sufficed crit (from 45-54% to 40-46%) and platelet levels (from 1.3-2.2 for both total leukocyte and platelet determinations by light million/cu mm to 1.0-1.7 million /cumm) (Chart 1). Circulating microscopy. Heparinized capillary tubes were used for micro- leukocytes showyeda reversal of the lymphoid-myeloid ratio to hematocrit determinations. Wright-Giemsa-stained blood films 1:4 and a shift to the left (5-15% immature granulocytes). and bone marrow imprints were prepared for differential leuko The bone marrow presented severe, predominantly granulo- cyte counts and studies of blood morphology. cytic hyperplasia with a shift to the left (Fig. 16), as well as pro Intact control mice (Group la) were sacrificed at ages com nounced megakaryocyte depression (Table 1). Megakaryocyte parable to those of the corresponding nonoperated tumor hosts. size remained within normal limits (20-50 fi in diameter). Sham-operated control mice (Group lò)were sacrificed 21 days About 5-20% of the granulocytes in both blood and bone mar following surgery. row were enlarged up to 1.5-fold and showed other morphologic Tissue samples were fixed in 10% neutral formalin, sectioned abnormalities (Fig. lo) commonly seen in tumor-associated at 5 n, and stained routinely with hematoxylin and eosin as well leukemoid reactions (5, 21, 27) as well as in pernicious anemia, as with (PAS)2 plus alcian blue. drug toxicity, and radiation disease states (36). The cytoplasm of Megakaryocytes were counted in 100 high power fields ( X 450) the abnormal granulocytes tended towards extreme basophilia in of 5-/í-thickPAS-stained sections of femoral and sternal bone both immature and mature cells and frequently presented ir marrow and of spleen—equivalent to 2.35 X IO5cu n of the fixed regular coarse granulation. The nuclei manifested swelling, hyper- tissue sample. segmentation, clumped and accessory chromatin, and occa Samples of blood, tumor tissue (with and without central sionally abnormal mitotic figures. necrosis), liver, and spleen were taken at autopsy, under aseptic The tumor size-tumor weight curve of the CE 1460 tumor was conditions, from 12 ~Fihybrid mice bearing CE 1460 MA CA and linear in transplanted and biphasic in recurrent (postexcision) cultured both aerobically and anaerobically on blood agar and in tumors (Chart 2). In the latter, it increased in a linear fashion up thioglycolate broth. Whenever necessary, further diagnostic cul to around the 3.5-gm level, then leveled off as the tumor began to ture media were used to identify any microorganisms present.
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